1. Introduction
Antibacterial resistance is one of the most serious threats to human health throughout the globe, causing at least 1.27 million deaths worldwide per year and being associated with nearly 5 million deaths in 2019 [
1]. To address this threat, the World Health Organization (WHO) has urged its member countries to take action to prevent the world from reverting to the pre-antibiotic era, as common infections are once again becoming able to kill, since as early as ten years ago [
2]. As time passes, people have realized that these constant efforts must be strengthened in two aspects, establishing a so-called “shield and spear” approach to curb the rise and development of antibacterial resistance. Here, the metaphorical “shield” refers to measures to delay the continuous emergence and spread of antibacterial resistance, such as preventing infections, reducing antibiotic overuse and misuse, and controlling transmission. Indeed, some progress has been made in slowing down the resistance rates of certain pathogens. However, a lack of new antibiotics—the metaphorical “spear”—largely compromises efforts to contain drug-resistant infections [
3]. A more aggressive measure, in comparison with limiting the use of antibiotic to prevent the occurrence of resistance, is the discovery and development of new drugs to directly treat infections caused by drug-resistant pathogens, especially the “superbugs” characterized by multi-drug resistance (MDR). In 2017, the WHO released a priority list of bacterial pathogens requiring the development of new antibacterial drugs [
4]. According to the list, the 12 bacterial families that pose the greatest threat to human health, mainly MDR pathogens, are divided into three key priorities based on the urgency and necessity for new and effective antibiotic treatments. Among these, the “critical-priority” pathogens are carbapenem-resistant
Acinetobacter baumannii (
A. baumannii) (CRAB), carbapenem-resistant
Pseudomonas aeruginosa (
P. aeruginosa) (CRPA), and carbapenem-resistant and third-generation cephalosporin Enterobacteriaceae. “High-priority” pathogens include vancomycin-resistant
Enterococcus faecium (
E. faecium), methicillin-resistant and vancomycin-intermediate or -resistant
Staphylococcus aureus (
S. aureus), clarithromycin-resistant
Helicobacter pylori (
H. pylori), fluoroquinolone-resistant
Campylobacter, fluoroquinolone-resistant
Salmonella spp., and third-generation cephalosporin and fluoroquinolone-resistant
Neisseria gonorrhoeae. “Medium-priority” pathogens include penicillin-non-susceptible (penicillin-intermediate and -resistant)
Streptococcus pneumoniae (
S. pneumoniae) (PNSP), ampicillin-resistant
Haemophilus influenzae, and fluoroquinolone-resistant
Shigella spp. So far, this list has been widely used as a guideline for the research and development (R&D) of new antibacterial treatments by those organizations and institutions responsible for policy formulation, funding, investment, research, and development in many countries, including China. In addition, other frequently occurring antibiotic-resistant pathogens such as
Mycobacterium tuberculosis (Mtb), non-tuberculosis mycobacteria (NTM), and
Clostridium difficile (
C. difficile) are regarded by experts from the WHO and countries such as the United States, India, and China as priorities that require urgent investment in new drugs, owing to their major public health and clinical implications. Recently, several high-quality reviews on global clinical antimicrobial pipelines have been published, providing updated information on the progress of new clinical candidates against the priority pathogens listed above [
5], [
6], [
7], [
8], [
9], [
10]. However, these reviews’ information on the approval status and clinical pipelines of antibacterial drugs originally developed in China is incomplete or requires updating.
China bears a heavy burden of antibacterial resistance due to the abuse and overuse of antibiotics in human healthcare systems and agricultural industry in the past decades [
11]. Furthermore, tuberculosis (TB) remains a major problem in China, with a relatively high prevalence of MDR and extensively drug-resistant (XDR) Mtb strains [
12]. In the context of the high rate of antibiotic resistance, the selectivity or availability of effective antibacterial drugs in clinical infection treatments is increasingly limited, impelling China to adopt national action plans to promote the development of more antibacterial drugs—especially new products with traditional or non-traditional modes of action (MoAs) [
13]. As a response in 2008, the Ministry of Science and Technology (MoST), the National Development and Reform Commission (NDRC), the Ministry of Finance (MoF), and the National Health Commission (NHC) of the People’s Republic of China jointly launched a National Mega-Project for Innovative Drugs (NMPID; also known as the National Science and Technology Major Project for Significant New Drugs Development) to encourage the R&D and industrialization of innovative drugs, including antimicrobials [
14]. From 2008 to 2020, the NMPID entirely supported more than 3000 programs associated with the treatment of ten major disease categories endangering the health of Chinese citizens (i.e., malignant tumors, cardiovascular/cerebrovascular diseases, neurodegenerative diseases, diabetes, mental diseases, autoimmune diseases, infections by antibiotic-resistant pathogens, TB, viral infectious diseases, and other frequently occurring diseases) [
15]. Actuated by the NMPID and other national actions to reduce the incidence of antibacterial resistance, pharmaceutical enterprises, sponsors, and investors have increased their investment in antibacterial drug R&D in the past decade, and there has been a significant increase in the number of clinical antibacterial drug pipelines in China. In addition, as National Medical Products Administration (NMPA; formerly the Food and Drug Administration or CFDA) of the People's Republic of China has been paying more attention to products used to prevent and treat infections in the last few years, especially since the outbreak of coronavirus disease 2019 (COVID-19), innovative anti-infective drugs have been accelerated or prioritized for review and approval [
16].
In this review, we summarize the latest progress in new antibacterial drugs initially developed by Chinese pharmaceutical companies and/or institutions that were approved for marketing and are under clinical trial evaluation in China from January 1, 2019, to June 30, 2023. It should be noted that clinical drug candidates whose development plans have been terminated or have not been updated in the past three years are excluded. The new drugs described herein refer to new chemical entities, biological entities, or combinations that have not previously been licensed market authorization for human medicinal use anywhere in the world. In addition, new antibacterial agents that have been granted marketing authorization or are undergoing multicenter clinical evaluations in China but are developed by international pharmaceutical companies outside China are excluded from this analysis. As most of these new antimicrobial agents are currently undergoing clinical development, data on efficacy, pharmacokinetics (PK), and safety from human trials are not yet available. For the new drugs or drug candidates displayed in this review, rather than focusing on an in-depth and systematic description of each agent, we provide a snapshot of publicly available progress during their development. Furthermore, we mention—if this information is available—which priority pathogens (from the WHO list of priority pathogens and others) the antimicrobial agents can treat and trace whether or not they have been funded by the national innovative drug development project, the NMPID.
2. Inclusion criteria of clinical antibacterial pipelines
The antibacterial drug pipelines involved in this review are all products that have been initiated and developed by Chinese pharmaceutical companies and/or institutions, including antibacterial agents jointly developed by domestic pharmaceutical enterprises and international companies, institutions, or individuals at an early stage, but excluding those patented drugs or generic equivalents licensed from branded companies abroad. Aside from the antibacterial agents that gained market authorization from the NMPA between January 1, 2019, and June 30, 2023, we predominantly analyze the antibacterial pipelines that are currently conducting new drug application (NDA) and being evaluated in phases-1 to -3 clinical trials in China. The updated data on clinical antimicrobial pipelines come from the following sources: the drug database available on the NMPA’s official website; the commercial database INSIGHT: China Pharma Data; news and announcements on the websites of pharmaceutical companies and institutions; academic literature in Chinese and English; the WHO Antibacterial Pipeline Report (2021); and NMPID reports or abstracts [
17]. Considering that some companies may be particularly careful to keep their projects confidential and have not applied for funds, we also complemented and verified missing information through personal communications. The antibacterial drugs presented in this review include agents with various administration routes, including oral, intravenous (IV), intramuscular, inhalation, skin, and mucous membrane administration, for the treatment of priority pathogens against which new antibacterial agents are urgently needed for treatment in China. This review does not include new formulations and prodrugs of approved antibacterial agents, unless they allow new antibacterial uses that were previously impossible. Antibodies and antisera with antibacterial properties are also beyond the scope of this review.
3. Antibacterial drugs approved by the NMPA since 2019
Carrimycin—once known as shengjimycin, biotechspiramycin, and bitespiramycin—is a new 16-membered macrolide antibiotic complex structurally related to spiramycin (SPM) that was originally developed by Dai et al. [
18] from the Institute of Medical Biotechnology (IMB), Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), through synthetic biology techniques. As an inhibitor to the 70S ribosome, the functional class of carrimycin is not new, but its multiple main components are closely related to 4″-
O-isovalerylspiramycin (iso-SPM), among which iso-SPMs III, II, and I account for 37.7%, 22.5%, and 7.4%, respectively. Compared with SPM (containing the major components SPMs III, II, and I), the three components of carrimycin all contain an additional 4″-
O-isovaleryl group at the terminal carbohydrate residue (
Fig. 1), which makes carrimycin more lipophilic and active. The minimum inhibitory concentrations (MICs) of carrimycin against
Chlamydia trachomatis,
Chlamydia pneumoniae,
Ureaplasma urealyticum, and
Mycoplasma pneumoniae are in the range of 0.03-0.5 μg∙mL
−1, making them equivalent to those of azithromycin for these atypical pathogens. Gratifyingly, a phase-3 clinical trial showed that carrimycin had better efficacy and safety than azithromycin. As a result, oral tablets of carrimycin were approved by the NMPA of the People’s Republic of China on June 24, 2019, for the treatment of acute tracheobronchitis, acute sinusitis, and other upper/lower respiratory tract infections caused by bacteria, such as
S. pneumoniae,
Haemophilus influenzae, and
Moraxella catarrhalis, and atypical pathogens, including
Mycoplasma and
Chlamydia species (
Table 1 [
19], [
20]) [
21]. Intriguingly, the latest research demonstrated that carrimycin also exhibited broad-spectrum antiviral activity against human coronaviruses (HCoVs), including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and its therapeutic efficacy and safety in hospitalized COVID-19 patients is currently under a randomized, multicenter, placebo-controlled, double-blind phase-3 study [
22], [
23]. Experiments at the cell level, such as the time-of-addition test, pseudotyped lentiviral infection assay, and metabolic labeling study, have all shown that carrimycin can directly inhibit viral RNA synthesis and prevent the infection of multiple HCoVs by targeting one or multiple post-entry replication events, resulting in antiviral effects similar to those of the HCoV RNA polymerase (RNAP) inhibitor remdesivir (RDV) [
22].
Contezolid (MRX-1), a new oral oxazolidinone compound, was granted a marketing license on June 1, 2021, from the NMPA of the People's Republic of China to treat complex skin and soft tissue infections (cSSTI) caused by Gram-positive bacteria (
Table 1). Preclinical evaluations suggested that the chemical structure of contezolid (
Fig. 2) provided less adverse effects, such as myelosuppression and monoamine oxidase (MAO) inhibition, than linezolid (LZD), the first oxazolidinone antibiotic approved by the US Food and Drug Administration (FDA) [
24]. Susceptibility testing data from the 2015 SENTRY Antimicrobial Surveillance Program suggested excellent activity of contezolid against the MDR pathogens listed by the WHO as high and medium priorities, such as vancomycin-resistant
Enterococci (VRE), methicillin-resistant
S. aureus (MRSA), and PNSP, with the minimum inhibitory concentration for 90% of organisms (MIC
90) of 1 μg∙mL
−1. In addition, its promising activity against Mtb, including isoniazid (INH)-resistant strains (MIC
90 1 μg∙mL
−1), has been demonstrated [
25]. According to the data from multicenter phases-2 and -3 clinical studies conducted in China, contezolid was found to be noninferior to LZD for the treatment of cSSTI patients but showed better safety than LZD in terms of adverse hematological effects [
26], [
27]. Currently, additional multinational phase-3 clinical studies evaluating the efficacy and safety of contezolid and its IV form, contezolid acefosamil (MRX-4, a prodrug of contezolid,
Fig. 2), for acute bacterial skin and skin structure infections (ABSSSI), as well as for diabetic foot infections, are underway [
28]. Moreover, the less toxic effects of contezolid and its excellent activity against drug-resistant Mtb (DR-Mtb) may allow for its use in treating MDR/XDR-TB [
29], [
30].
4. Antibacterial agents in clinical trials or with NDA submitted
One biologic agent—namely, recombinant lysostaphin (r-lysostaphin)—for which an NDA has been submitted to the NMPA of the People's Republic of China and another 17 new antibacterial chemical entities or combinations that are being evaluated in clinical trials in phases-1 to -3 were identified by this review’s cutoff date (
Table 2 [
19], [
31], [
32], [
33], [
34], [
35], [
36], [
37], [
38], [
39] and
Table 3 [
19], [
40], [
41], [
42]). Among the 17 new antibacterials under clinical trials, there are ten drug candidates that are expected to treat infections caused by the WHO priority pathogens, six for Mtb, and one for other drug-susceptible (DS) and DR bacteria (
Fig. 3(a)). Drugs such as TNP-2198, whose expected utility is to treat infections caused by both WHO priority pathogens and other important pathogens (e.g.,
C. difficile), are only recorded in the former antibacterial category.
Lysostaphin is a bacterial antimicrobial protein (also known as bacteriocin) of 246 amino acids (molecular weight (MW) ≈ 27 kDa) originally isolated from coagulase-negative
staphylococci (CNS), with potent cell-wall lytic—and thus bactericidal—activity against the WHO priority pathogen
S. aureus [
31]. Lysostaphin belongs to a class of monomeric zinc-containing endopeptidases, and its bacteriolytic action is primarily due to the cleavage between the third and the fourth Gly residues of the pentaglycine cross-bridge that is present almost exclusively in the cell-wall peptidoglycan of
S. aureus [
43]. The r-lysostaphin from Shanghai Hi-Tech Bioengineering Co., Ltd., is recombinantly expressed in
Escherichia coli (
E. coli), and its topical administration agent is expected to treat superficial wound and burn infections caused by
S. aureus in hospitals and communities. Although the phases-1 to -3 clinical trial data of r-lysostaphin as a new topical medicine has yet to be publicly disclosed, disinfection products based on the recombinant bacteriocin, such as a spray and a mouthwash with the respective trade names BaiKeRui and NewClean (XinJingJie), have long been commercially available in China as a means of disinfecting or sanitizing the skin and mucous membranes (nasal and oral cavities) of adults and children from carriage or colonization of
S. aureus [
44].
Of the ten new antibacterial drugs under clinical investigation that are expected to have activity against at least one of the WHO priority pathogens, three, three, and four are respectively in phases-1, -2, and -3 (
Fig. 3(a)). Classifying and calculating all ten new antibiotics according to their antimicrobial spectrums reveals that two and six of them are expected to treat infections caused by Gram-positive cocci and Gram-negative bacilli, respectively, while the other two are agents with broad-spectrum antibacterial properties (
Fig. 3(b)). Number of drug candidates according to their compound classes and number of drug candidates with activity against
M. tuberculosis according to their compound classes were showed in
Figs. 3(c) and
(d). Among the three drugs in phase-3, two dual-acting antibiotic hybrids developed by TenNor Therapeutics—namely, TNP-2092 and TNP-2198—will target implanted-medical-device-related infections caused by Gram-positive cocci, including MRSA and infections caused by microaerophilic or anaerobic bacteria, respectively. Another drug is a new β-lactamase inhibitor (BLI)-carbapenem combination, funobactam (XNW4107) plus imipenem-cilastatin. It is developed by Sinovent and is being evaluated to treat infections due to Gram-negative bacilli.
5. Antibacterial agents in phase-3 development with activity against WHO priority pathogens
TNP-2092, also known as CBR-2092, is a conjugate of rifamycin and fluoroquinolone (
Fig. 3(e)) with dual action. It was first synthesized by Cumbre Pharmaceuticals in the United States [
32]. With the dissolution of Cumbre Pharmaceuticals in 2009 and its acquisition by TenNor Therapeutics, TNP-2092 was taken over by the Chinese pharmaceutical company in the early stage of development, thus meeting the inclusion criteria for this review (see Section 2) [
45]. TNP-2092 comprises ciprofloxacin- and rifampin (RFP)-derived pharmacophores, but the developer indicated that the antibiotic hybrid is superior to RFP plus ciprofloxacin for a number of reasons [
32], [
46]: ① It possesses potent and balanced triple-targeting activity against RNAP, DNA gyrase, and topoisomerase IV; ② there are no potential problems due to unfavorable PK asynchrony, which regularly occurs in antibiotic cocktail approaches; ③ it is not a substrate for efflux pumps such as NorA or MepA and therefore retains its activity against resistance mediated by mutations of the efflux system; and ④ there are no observed safety concerns related to constituent elements such as hERG inhibition and the induction of CYP3A4 isoenzyme. In addition, the quinazolinone core exhibits activity against the ParCS80F variant of topoisomerase IV, the activity that is not retained by ciprofloxacin, which provides an explanation for the activity of TNP-2092 against bacterial isolates that are resistant to ciprofloxacin alone or in combination with RFP [
47]. Compared with RFP and ciprofloxacin alone or in combination, TNP-2092 exhibits equivalent or better
in vitro and
in vivo activity against planktonic and biofilm forms of Gram-positive bacteria—including
S. aureus and CNS, which often lead to implanted-medical-device-associated infections due to biofilm colonization.
In vitro studies showed that the minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and minimum biofilm bactericidal concentration (MBBC) values of TNP-2092 against prosthetic joint infections (PJIs)-associated
Staphylococci including MRSA and methicillin-resistant CNS (MRCNS) isolates were as follows: an MIC
50s/
90s of ≤ 0.0075-0.015/0.008-0.5 μg∙mL
−1; an MBC
50s/
90s of 0.015-0.5/0.125-4 μg∙mL
−1; and an MBBC
50s/
90s of 0.06-0.5/0.25-2 μg∙mL
−1 [
32], [
45], [
46], [
47], [
48]. By the end of 2020, the powder for IV injection of TNP-2092 had successively received qualified infectious disease products (QIDPs), fast track, and orphan drug (for the treatment of bacterial PJIs) designations from the US FDA [
49]. An IV formulation of TNP-2092 is currently under phase-3 studies for the treatment of implanted-medical-device-associated bacterial biofilm infections, including PJIs caused by MRSA, in the United States [
50]. Meanwhile, the IV or oral dosing of TNP-2092 is also in the advanced or late clinical development phases (phase-2/-3 for the treatment of ABSSSI, cirrhosis hepatic encephalopathy, and irritable bowel symptom-diarrhea (IBS-D)) in the United States and China [
46], [
49].
Aside from TNP-2092, the conjugate of rifamycin and metronidazole TNP-2198 is another dual-acting antibiotic hybrid being developed by TenNor Therapeutics. This hybrid contains a rifamycin core that is fused at position 3 to metronidazole through a linker with an ethylene group (
Fig. 3(e)) and is intended to inhibit the synthesis of RNA by binding to the rifamycin binding site on RNAP and the DNA template-strand in the RNAP active-center cleft. TNP-2198 exhibited broad-spectrum antibacterial potential against a wide range of aerobic, microaerophilic, and anaerobic bacteria, including
S. aureus (MIC
range 0.015-0.03 μg∙mL
−1),
H. pylori (MIC
90s 0.125-0.5 μg∙mL
−1),
C. difficile (MIC
90 1 μg∙mL
−1),
G. vaginalis (MIC
90 0.06 μg∙mL
−1), and Mtb (MIC 0.016 μg∙mL
−1) [
35], [
51]. A preclinical study showed that the conjugation of the rifamycin and nitroimidazole pharmacophores in TNP-2198 resulted in significant synergistic activity, which was well reflected in its greater activity than a 1:1 molar mixture of the parent rifamycin and nitroimidazole and its activity against strains resistant to both rifamycin and nitroimidazoles [
35]. The high tissue and content (or secretion) distributions of TNP-2198 in the stomach, large intestine, and vagina via IV and oral dosing make it suitable for the treatment of gastrointestinal tract infections or bacterial vaginosis (BV). At the end of 2022, TenNor Therapeutics announced that it had successfully completed phase-2 studies on the oral administration of TNP-2198 for treatment of
H. pylori infection and had entered phase-3 trials in China. The latest information on the official website of TenNor Therapeutics is that TNP-2198 has been granted QIDP status by the US FDA for the treatment of
H. pylori infection [
52]. However, the PK, pharmacodynamics (PD), and safety of TNP-2198 in the clinical phase 1/2 have yet to be publicly disclosed.
XNW4107 is a novel non-β-lactam BLI containing a diazabicyclooctane (DBO) scaffold (
Fig. 3(e)). It belongs to the second generation of BLIs, represented by avibactam and relebactam, and restores the activity of β-lactams against a wider range of bacteria producing Ambler classes A, C, and D serine β-lactamases that are not susceptible to first-generation inhibitors containing a classic β-lactam ring [
53]. XNW4107 has no antibacterial activity as a monotherapy and is being developed in combination with imipenem-cilastatin to treat bacterial infections, including those caused by carbapenem-resistant bacilli. A preclinical study conducted at Peking University First Hospital in Beijing, China, revealed that XNW4107 in combination with imipenem displayed potent
in vitro activity against CRAB, and particularly against CRAB (
n = 106) and
Klebsiella pneumoniae (K. pneumoniae) (
n = 54), with respective MIC
90s of 8 and 2 μg∙mL
−1, which were 16- and 128-fold lower than the MIC
90s of imipenem alone. According to the Clinical and Laboratory Standards Institute (CLSI) resistance breakpoint (≥ 8 mg∙L
−1), the resistance rates of imipenem-non-susceptible and -resistant isolates of
A. baumannii,
P. aeruginosa, and
K. pneumoniae to imipenem decreased from 91.1%-100% to 3.7%-37.6% in the presence of XNW4107 at 8 μg∙mL
−1. Compared with avibactam and relebactam, XNW4107 exhibited similar
in vitro inhibition activity against KPC-2 (a class A enzyme), as well as AmpC_AB and AmpC_PA (class C enzymes), with an IC
50 range of 0.13-0.88 μmol∙L
−1. The developer was inspired by the fact that the ability of XNW4107 to inhibit OXA-24/40-like β-lactamases (class D enzymes) is much superior to those of avibactam and relebactam, with an IC
50 of approximately 1.4 μmol∙L
−1 for XNW4107 vs 27.7-38.7 μmol∙L
−1 and > 200 μmol∙L
−1 for avibactam and relebactam, respectively [
33]. However, there is no evidence to suggest that XNW4107 can inhibit metallo-β-lactamases (MBLs; class B enzymes). At present, the combination of XNW4107 with imipenem-cilastatin to treat hospital-acquired and ventilator-associated pneumonia (HAP/VAP), as well as complicated urinary tract infections (cUTIs) including pyelonephritis caused by Gram-negative bacteria, is under phase-3 studies in the United States (NCT05204368) and China (CXHL2200420).
6. Antibacterial agents in phase-2 development with activity against WHO priority pathogens
FL058, also known as WX189, is a new non-β-lactam BLI based on a DBO structure (
Fig. 3(e)). It was originally synthesized by WuXi AppTec and subsequently transferred to Qilu Pharmaceutical for development. According to the limited
in vitro and
in vivo data from the patent on the compound (CN 109311881B), FL058 not only shows activity against carbapenem-resistant Enterobacteriaceae (CRE) producing KPC-2 or OXA-181 (class D enzyme), like most other DBOs, but also exhibits activity against some
K. pneumoniae strains expressing MBLs such as NDM-1 (a class B enzyme), which are not susceptible to avibactam [
36], [
54]. Currently, an IV administration of a combination of FL058 and meropenem to treat cUTI including acute pyelonephritis (AP) caused by Enterobacteriaceae is under phase-2 development in China (CTR20212255) [
55].
Litazolid (LT-01) is a novel oxazolidone antibiotic (
Fig. 3(e)) that was initially developed in an attempt to reduce the bone marrow inhibitory toxicity of existing oxazolidinones such as LZD while maintaining their efficacy [
56], [
57]. An
in vitro antibacterial experiment with 859 isolates of clinical Gram-positive bacteria—involving 110 MRSA strains, 116 methicillin-resistant
Staphylococcus epidermidis (MRSE) strains, 37 PNSP strains, 14 vancomycin-resistant
E. faecalis (VREFA) strains, and 21 vancomycin-resistant
E. faecium (VREFM) strains—demonstrated that the antimicrobial activity of litazolid against the tested pathogens was similar to that of LZD, with both MIC
90s at 0.25-4 μg∙mL
−1 [
58]. In the treatment of systemic infections caused by VRE and acute pneumonia caused by MRSA in mice, the respective 50% effective doses (ED
50; i.e., the dose that protected 50% of the mice from death) of litazolid and LZD after infection were 4.441 and 9.550 mg∙kg
−1 for litazolid and 6.656 and 13.843 mg∙kg
−1 for LZD, reflecting the similar antibacterial effects of the two drugs
in vivo [
59]. Recently, the developer, Guangdong Jincheng Jinsu Pharmaceutical, briefly mentioned the good drug tolerability and safety profile of litazolid in its phase-1 clinical trial and pointed out that no adverse events of bone marrow suppression were observed when the drug was administered to patients at a single dose of up to 1600 mg [
56]. Since the end of 2022, the dry suspension of litazolid for the treatment of infections due to Gram-positive bacterial pathogens has moved into a phase-2 trial in China (CXHL 2018L02182) [
60].
Zifanocycline (KBP-7072) is a novel semisynthetic aminomethylcycline antibiotic (
Fig. 3(e)) with broad-spectrum activity against Gram-positive and Gram-negative pathogens that is being developed by Shandong Hengli. According to recent susceptibility testing data, including those from the 2019 SENTRY Antimicrobial Surveillance Program, zifanocycline demonstrated potent
in vitro activity against many MDR-pathogens, even those in the WHO priority list, including: CRAB (MIC
50/
90 0.5/1 μg∙mL
−1); expanded-spectrum β-lactamase (ESBL) phenotype
E. coli (MIC
50/
90 0.25/1 μg∙mL
−1); ESBL phenotype
K. pneumoniae (MIC
50/
90 0.5/2 μg∙mL
−1); ceftazidime-non-susceptible
Enterobacter cloacae species complex (MIC
50/
90 0.25/0.5 μg∙mL
−1); tetracycline-resistant
Enterobacterales (MIC
50/
90 1/4 μg∙mL
−1); MRSA (MIC
50/
90 0.06/0.12 μg∙mL
−1); tetracycline-resistant
S. aureus (MIC
50/
90 0.06/0.25 μg∙mL
−1); vancomycin-non-susceptible
E. faecium (MIC
50/
90 0.03/0.03 μg∙mL
−1); penicillin-, erythromycin-, and tetracycline-resistant
S. pneumoniae (MIC
50/
90 ≤ 0.015/0.03 μg∙mL
−1); and macrolide-resistant
S. agalactiae (MIC
50/
90 ≤ 0.015/0.03 μg∙mL
−1) [
61], [
62], [
63]. The dose-proportional PK/PD properties in both animal models and phase-1 clinical studies support the suitability of zifanocycline for once-daily oral and IV administration [
64], [
65]. Through a 10-day multiple ascending dose study in healthy volunteers, the likely therapeutic dose of zifanocycline was found to be ≤ 200 mg∙d
−1 [
64]. The PK/PD and probability of target attainment (PTA) analysis indicated that zifanocycline would be efficacious for Gram-positive pathogens at a dose level of 50 mg and for Gram-negatives (
A. baumannii) at a dose level of 200 mg [
61], [
65]. In 2016, zifanocycline was granted the QIDP and fast-track designations from the US FDA [
66]. The oral and IV formulations of the new drug candidate have entered phase-2 development for the treatment of ABSSSI, community-acquired bacterial pneumonia (CAP), and complicated intra-abdominal infections (cIAI) in the United States and China [
61], [
67].
7. Antibacterial agents in phase-1 development with activity against WHO priority pathogens
Due to the emergence and development of MDR (and even XDR) Gram-negative pathogens in healthcare and community settings, polymyxins have reemerged as a last-resort treatment against infections caused by these “superbugs.” However, the use of the only polymyxins currently available in clinical practice, polymyxin B (PMB) and colistin (polymyxin E), is greatly limited by their nephrotoxic side effects and narrow therapeutic windows, so it is attractive for developers to generate new, safer polymyxins with comparable or better efficacy than PMB and colistin [
38]. MRX-8 is a new PMB analog adopting a prodrug approach that is being developed by MicuRx. Compared with PMB, it carries a fatty acyl tail linked via an ester bond, which allows for de-esterification to a less toxic metabolite without loss of antimicrobial activity. In preclinical studies that evaluated the
in vitro activity of MRX-8 and comparators (i.e., colistin and PMB) against a large set of Gram-negative clinical isolates (
n = 2079) collected from 129 hospitals and medical centers in the United States and China in 2017-2020, MRX-8 exhibited slightly more potent or nearly identical antimicrobial activities compared with colistin and PMB against almost all of the Gram-negative species and groups tested, including MDR and carbapenem-resistant subsets. The MIC
50/90s of MRX-8 against CRAB, CRPA, and CRE represented by meropenem-resistant
K. pneumoniae and
E. coli were 0.5/1, 0.5-1/1, and 0.06-0.125/0.125-0.5 μg∙mL
−1, respectively [
68], [
69]. In the PK/PD study of MRX-8 and PMB against a variety of Gram-negative pathogens in neutropenic mouse thigh and lung infection models, both agents displayed a linear maximum concentration of drug in serum (
Cmax) and area under the drug concentration-time curve from 0 h to infinity (AUC
0-∞) values over a broad dosing range of 0.156 to 10 mg∙kg
−1 of body weight and had similar AUC
0-∞ exposure (0.22-12.64 vs 0.12-13.22 mg∙h∙L
−1). A dose-response analysis of MRX-8 against
E. coli ATCC25922 revealed that both the free-drug
Cmax/MIC and AUC/MIC ratios were strongly associated with its therapeutic effect. In thigh infection models with
E. coli,
P. aeruginosa,
K. pneumoniae, and
A. baumannii, both MRX-8 and PMB exhibited increased antimicrobial effect with increasing doses. Although the free-drug AUC (
fAUC)/MIC ratios achieving net stasis for both drugs against
E. coli and
K. pneumoniae were similar, the ratio was numerically smaller for MRX-8 than for PMB against
P. aeruginosa and
A. baumannii, suggesting that MRX-8 exhibited enhanced efficacy against the latter two species. In the lung infection model, MRX-8 was observed to show more favorable
in vivo activity than PMB when dosed to achieve similar
fAUC exposures over the study period [
70]. Although a phase-1 trial of MRX-8 began in the United States in November 2020 and is now almost completed (NCT04649541), safety, tolerability, and PK data from a human trial of MRX-8 are not yet available [
71]. Another phase-1 clinical trial of MRX-8 administered intravenously in healthy Chinese subjects is ongoing and expected to be completed in 2023 [
72]. A detailed structure of MRX-8 has not been publicly disclosed.
Commercially available colistin (polymyxin E) is a mixture of at least 11 individual components with branched and non-branched N-terminal fatty acyl groups. Polymyxin E
1 (colistin A) and polymyxin E
2 (colistin B) are two major components accounting for approximately 85% of the mixture (colistin), with the proportion of the latter being much less than that that of the former in the total contents (5%–20% vs 50%–75%) [
38], [
73]. According to the limited information in the literature on the chemical biology of polymyxin-induced nephrotoxicity, polymyxin E
2 has a three-fold lower apoptosis-inducing effect on human HK-2 cells (a proximal tubular cell line derived from normal kidney) than polymyxin E
1, despite there being only a difference of one methylene group (
$-\mathrm{CH}_{2}-$) between the two components [
38]. Few studies compare the
in vitro and
in vivo antibacterial activity of polymyxin E
2, polymyxin E
1, and/or colistin. However, a study in the 1980s showed that, even though polymyxin E
2, polymyxin E
1, and colistin showed identical
in vitro activity against most of the tested bacteria, the MICs of polymyxin E
2 against part of
K. pneumoniae and
P. aeruginosa strains were half those of polymyxin E
1 and colistin [
74]. In summary, previous studies have shown that polymyxin E
2 is a single-component drug with higher safety and/or stronger antibacterial activity than the marketed drug colistin. Polymyxin E
2 methane sulfonate, a prodrug of polymyxin E
2, was initially developed as a new drug candidate by the China State Institute of Pharmaceutical Industry and later transferred to Chiatai Tianqing for further development. A phase-1 clinical trial aiming to assess the tolerability, safety, and PK profile of polymyxin E
2 methane sulfonate for injection is currently being conducted in healthy Chinese adults (CXHL1700355).
ASK0912 (IMB-0912) is a new polymyxin derivative that contains the same peptide cycle as the naturally occurring polymyxin S
1 but has a fatty acyl tail of 6-methylheptanoic acid (6-MHA) rather than 6-methyloctanoic acid (6-MOA) [
75], [
76]. Relative to the polymyxins with five positive charges (i.e., PMB and colistin), ASK0912 has a polar amino acid D-serine (D-Ser) instead of L-diaminobutyric acid (L-Dab) with a positive charge at position 3 in the peptide cycle, which results in four positive charges being carried by ASK0912. ASK0912 was initially synthesized and identified as a peptide antibiotic candidate due to its increased efficacy and decreased toxicity by Cui et al. [
76] at the IMB; it was then transferred to Aosaikang (ASK) Pharm for new drug development [
76], [
77]. In an analysis of the structure-activity relationship (SAR) and structure-toxicity relationship (STR) of polymyxins, ASK0912 displayed enhanced
in vitro activity against
E. coli,
K. pneumoniae, and
A. baumannii, with MIC values of 0.125-0.5 μg∙mL
−1 (compared with MICs for both PMB and colistin of 0.5-1 μg∙mL
−1). It also showed a noticeably reduced toxicity profile, with a 50% cytotoxicity concentration (CC
50) of (756 ± 29) μg∙mL
−1 in Vero cells (vs (103 ± 13) and (154 ± 13) μg∙mL
−1 for PMB and colistin, respectively) and a lethal dose for 50% of animals (LD
50) of 17.0 mg∙kg
−1 in Institute of Cancer Research (ICR) mice (vs 6.9 and 8.5 mg∙kg
−1 for PMB and colistin, respectively). All these advantages are thought to be associated with the characteristics of ASK0912, such as the four positive charges it carries [
76]. ASK0912 was also found to exhibit more potent
in vivo antimicrobial activity than PMB in a mouse model of systemic infection using the NDM-1-producing strain
K. pneumoniae ATCC BAA-2146, with a ED
50 of 0.9 mg∙kg
−1 for ASK0912 vs 2.2 mg∙kg
−1 for PMB [
77]. In September 2022, ASK0912 entered phase-1 development in Shanghai, China (CTR20222379) [
78].
HRS-8427 is an injectable cephalosporin antibiotic being developed by Jiangsu Hengrui Pharmaceuticals. However, its detailed structure has not been disclosed, and other publicly available information is also very limited. Based on a search for Chinese patents, we speculate that HRS-8427 may be an analog of cefiderocol, an iron-chelator siderophore cephalosporin. The developer has indicated that the antibiotic is aimed at the treatment of severe drug-resistant Gram-negative bacterial infections such as UTI and HAP/VAP [
79].
8. Antibacterial agents in phase-3 development with anti-tuberculosis activity
Bedaquiline (BDQ) has been listed as the preferred option for rifampin-resistant TB (RR-TB) and MDR-TB by the WHO since 2018 because of its unique mechanism of action (i.e., inhibiting the ATP synthase of Mtb) and the treatment success of regimens containing it [
80]. However, the widespread clinical use of BDQ has been limited by its increased risk of unexplained mortality and toxicity such as QTc prolongation, phospholipidosis, and hepatotoxicity. In addition, the high price of BDQ places a financial burden on patients and TB control. Therefore, the development of safer and more affordable BDQ-based new drugs with comparable potency has been a choice for pharmaceutical companies [
81], [
82]. Sudapyridine (WX-081) is a new diarylpyridine analog (
Fig. 3(e)) that was initially synthesized by WuXi AppTec through substituting the bromoquinoline of BDQ with a 5-phenylpyridine. The compound was then obtained by Shanghai Jiatan Biotech and introduced to the clinical development stage in 2018. Preclinical evaluation of WX-081’s
in vitro antimycobacterial activity conducted in China demonstrated that the MICs of WX-081 were generally 2- to 4-fold higher than those of BDQ, with MIC
50/90s of 0.083/0.152-0.25/0.5 and 0.029/0.043-0.125/0.25 μg∙mL
−1 for WX-081 and BDQ, respectively, against the tested Mtb including MDR strains [
81], [
82], [
83]. The
in vivo efficacy of WX-081 in reducing the bacterial load was nearly equivalent to that of BDQ at the same oral doses (5-20 mg∙kg
−1) in both acute and chronic TB infection models [
82], [
83]. The developer revealed that WX-081 possesses safety advantages and better lung exposure in comparison with BDQ. Indeed, a tissue distribution study in mice and rats demonstrated that WX-081 had about a 6-fold higher lung concentration than BDQ (857/337 ng∙g
−1 lung tissue vs 135/58.8 ng∙g
−1 lung tissue in mice/rats). In head-to-head safety studies, WX-081 demonstrated better safety and tolerability in rats and a lower risk of QTc interval prolongation in dogs when compared with BDQ. For example, in a 14-day good laboratory practice (GLP) toxicology evaluation using Beagle dogs with a daily dose of WX-081 and BDQ (200 mg∙kg
−1 for both), there were no qualitative electrocardiogram (ECG) changes for WX-081-treated dogs, but QTc interval prolongation by over 10% was observed in BDQ-treated dogs [
81]. Since April 2022, oral administration of WX-081 has been undergoing multicenter phase-3 clinical development for the treatment of MDR-TB (CTR20221162) after a successful phase-2 clinical trial (data not yet published) in China [
83]. Currently, preclinical studies on WX-081 against NTM such as
Mycobacterium intracellulare,
Mycobacterium avium, and
Mycobacterium kansasii are also ongoing in China [
84].
9. Antibacterial agents in phase-2 development with anti-tuberculosis activity
Pyrifazimine (TBI-166) is a new riminophenazine compound for MDR-TB treatment that is being developed jointly by the Institute of Materia Medica (IMM) from CAMS & PUMC and TB Alliance. TBI-166 was selected as an antimycobacterial candidate via a systematic screening with a SAR investigation of over 500 derivatives and was first reported in 2011 [
85]. Clofazimine, a riminophenazine compound, is an important drug option for individualized DR-TB therapy, and ongoing trials are exploring it as a cornerstone for novel, shorter regimens for both DS- and DR-TB. The exact mechanism of action of clofazimine against Mtb remains unknown, but its primary actions are believed to be related to interfering with membrane-associated physiological processes, including cellular respiration and ion transport. However, clofazimine-induced skin discoloration may significantly affect the quality of life and psychological well-being of patients and will ultimately interrupt their willingness to adhere to treatment. The synthesis, screening, and development of TBI-166 and other new derivatives are designed to target the requirements of reducing tissue discoloration and improving patients’ compliance while maintaining an antimycobacterial activity similar to that of clofazimine [
86]. The
in vitro antimicrobial profile of TBI-166 from preclinical studies revealed that its MICs against DS- and DR-Mtb strains ranged from < 0.005 to 0.15 μg∙mL
−1 and from 0.01 to 0.2 μg∙mL
−1, respectively, which were lower than those of clofazimine (0.026-0.633 and 0.075-0.844 μg∙mL
−1, respectively) [
85], [
87]. In a chronic murine infection model via low-dose aerosol of strain H37Rv, TBI-166 had an
in vivo efficacy against TB comparable to that of clofazimine at the same dose (20 mg∙kg
−1). Importantly, TBI-166 caused significantly less discoloration of adipose tissue and skin than clofazimine at all doses administered (10-80 mg∙kg
−1), despite its higher level of tissue accumulation [
87]. TBI-166 is now in its phase-2a evaluations, owing to its better efficiency and safety than clofazimine. Recently published data of preclinical studies on regimens containing TBI-166 reported that a TBI-166 + BDQ + pyrazinamide (PZA) regimen produced stronger bactericidal and sterilizing activity and a lower relapse rate than several other regimens, including the standard first-line HRZ regimen of INH + RFP + PZA, the BPaL regimen of BDQ + pretomanid (PMD) + LZD, and a TBI-166 + BDQ + LZD regimen, using BALB/c and C3HeB/FeJ murine TB infection models. The evaluators of the preclinical studies considered that the TBI-166-containing regimen exhibited sufficiently promising efficacy to warrant further investigation in phase-2b trials in China [
88], [
89].
TBI-223 is an oxazolidinone analog and another MDR-TB drug being jointly developed by the IMM from CAMS & PUMC and TB Alliance. Regimens containing LZD have been recommended by the WHO for the treatment of MDR- and XDR-TB due to their treatment success and reduced mortality. However, LZD may cause mitochondrial toxicity after long-term treatment. Thus, new oxazolidinones such as TBI-223 are being developed with the hope of achieving or exceeding the therapeutic benefits of LZD without its adverse effects [
90]. Compared with LZD, TBI-223 shows significantly reduced inhibition of mammalian mitochondrial protein synthesis (MPS), with an IC
50 of > 74 μmol∙L
−1 vs an IC
50 of 8 μmol∙L
−1 for LZD [
91]. Similarly, a comparison of the ratios of MPS inhibitory concentrations to MICs (MPS IC
50/MIC
50 and MPS IC
50/MIC
90) against Mtb or selectivity indices as an estimate of the therapeutic window for TBI-223 and LZD revealed that TBI-223 had much higher selectivity indices than LZD (MPS IC
50/MIC
50: 45 vs 16, MPS IC
50/MIC
90: 19 vs 5) [
92]. Correspondingly, TBI-223 exhibited better safety in various animal models. Taking a 14 day toxicity study in dogs as an example, no bone marrow toxicity of TBI-223 was observed at the highest dose of 150 mg∙kg
−1 given daily (AUC of 789 µg·h·mL
−1), while the safety margin for the bone marrow toxicity of LZD was < 1 (calculated by dividing the systemic AUC at the no-adverse-effect level by the exposure dose). A 14 day rat study also demonstrated that the no-observed-adverse-effect level (NOAEL) of TBI-223 for male and female rats was 200 and 75 mg·kg
−1·d
−1, respectively, which were much higher than a NOAEL of 20 mg·kg
−1·d
−1 for LZD. In addition, TBI-223 possesses advantageous ADME and PK properties in comparison with LZD, including improved stability in microsomes and hepatocytes, no induction or inhibition of major human cytochrome P450s (CYPs; 20% at 30 μmol·L
−1), high oral bioavailability with a reasonable distribution volume and moderate clearance (6.6 mL·min
−1·kg
−1 in dogs), an appropriate half-life (3 h in mice, 8 h in rats), and a projected human efficacious dose of 800 mg·d
−1 [
91]. Although preclinical studies suggested that TBI-223 is less potent than LZD against Mtb
in vitro, the wider therapeutic window of TBI-223 may enable comparable clinical efficacy with superior safety, making regimens containing the TBI-223 oxazolidinone suitable for the treatment of both DS- and MDR-/XDR-TB [
92], [
93]. Thus far, TBI-223 has successfully entered phase-2 clinical trials after the completion of phase-1 study (NCT03758612) [
91].
JBD0131 (WXWH0131), which is being developed jointly by Sichuan University and Jumbo Drug Bank, is a novel nitroimidazole with activity against MDR-Mtb. Nitroimidazoles are promising antimycobacterial agents known to inhibit the hypoxia-induced dormant phenotype, which makes them a potential treatment for latent TB infection and allows them to shorten the duration of anti-TB treatment. Although there are currently two nitroimidazole-based agents—delamanid and PMD (PA-824)—that have been approved by the regulatory agencies for MDR-TB treatment, neither is considered an ideal anti-TB drug because of shortcomings such as poor bioavailability due to low aqueous solubility, nonlinear clinical dose effects, and a tendency to prolong the QT interval. The development of JBD0131 and other new nitroimidazole analogs in China is aimed at meeting medical needs for a better nitroimidazole antimycobacterial agent as much as possible. Based on the currently available information, JBD0131 successfully completed its phase-1 evaluations (CTR20202308) in China in 2022 and entered phase-2 trials (CTR20223423) in April 2023 [
94], [
95]. JBD0131 exhibits improved physicochemical and PK properties over delamanid in terms of its lower molecular weight (401.42 vs 534.49), lower ClogP (2.40 vs 5.25), higher aqueous solubility (13.5 vs <1 μmol·L
−1 at pH = 7.4), higher cellular permeability (15.85 × 10
-6-20.92 × 10
-6 cm·s
−1 vs 0.09 × 10
-6-0.17 × 10
-6 in MDCK cells), and lower efflux ratio (0.76 × 10
-6 vs 1.90 × 10
-6 in MDCK cells). According to the PK parameters of JBD0131 from CD-1 mice via IV (0.6 mg·kg
−1) and oral (5 mg·kg
−1) dosing, it exhibited low clearance (9.42 mL·min
−1·kg
−1), adequate Vd (2.69 L·kg
−1), and long half life (
T1/2) (3.25 h) upon IV dosing, as well as good oral absorption as indicated by high plasma exposure (
Cmax 753 ng·mL
−1, AUC
0-last 7247 ng·mL
−1) after oral dosing. Comparing the MIC values of JBD0131 and delamanid against 40 strains of Mtb clinical isolates including DS and MDR strains, the
in vitro antibacterial activity of the former against Mtb appears to be lower than that of the latter, with MIC
50s/
90s of 0.011-0.012/0.030-0.035 μg·mL
−1 for JBD0131 vs 0.002/0.003-0.004 μg·mL
−1 for delamanid. However, with its good mouse PK, JBD0131 produced excellent
in vivo anti-TB efficacy, similar or even superior to delamanid in mouse tissues at doses of 10-100 mg·kg
−1, according to the bacterial load reduction or clearance in both acute and chronic TB infection models. Moreover, it is a safer agent than delamanid. JBD0131 and its major metabolite DM131 have significantly reduced hERG inhibitory activity
in vitro when compared with the delamanid metabolite DM6705 (hERG IC
50 >13.3 μmol·L
−1 vs 1.69 μmol·L
−1 and no QT interval prolongation was observed in 28-day GLP toxicology studies in dogs [
94].
10. Antibacterial agents in phase-1 development with anti-tuberculosis activity
OTB-658 (
Fig. 3(e)) is another oxazolidinone analog that is being developed by IMM and Beijing Union Second Pharmaceutical Factory. It is a conformationally constrained oxazolidinone candidate with the possible capacity to replace LZD in the treatment of TB, if its good activity, safety, and druggability profile obtained in preclinical evaluations can be further verified in clinical trials. OTB-658 exhibited a bacteriostatic effect 2- to 4-fold more potent than LZD on both DS- and MDR-Mtb tested strains
in vitro, with MICs of 0.008-0.167 vs 0.036-0.499 μg·mL
−1. The superior efficiency of OTB-658 in comparison with LZD was also observed in both acute and chronic murine TB models, which might partly benefit from the favorable PK profiles of OTB-658, such as appropriate absolute bioavailability (25.0% at an oral dose of 10 mg·kg
−1), a long half-life (> 500 min in human hepatocytes and > 14.7 h in mice), and excellent AUCs [
96], [
97]. Recent studies on the efficacy of replacing LZD with OTB-658 in anti-TB regimens in murine TB models demonstrated that a regimen of BDQ + PMD + OTB-658 (50 mg·kg
−1) and TBI-166 + BDQ + OTB-658 (50 and 100 mg·kg
−1) resulted in significantly reduced CFU counts of Mtb in the lung/spleen, with few relapses and no culture-positive lungs after eight weeks of treatment and after 4-8 weeks of treatment, respectively, which strongly supports its potential as a substitute candidate for LZD in further clinical evaluations. In 2020, OTB-658 was approved for clinical trials by the NMPA in China, and a phase-1 clinical trial (CTR20211895) to determine its safety in humans is ongoing [
98].
Aulimanid, also known as YF-49-92.MLS (
Fig. 3(e)), belongs to another novel nitroimidazole that is being developed by Nanjing Changao Pharmaceutical Science and Technology. It is undergoing its phase-1 clinical trial in China as a drug candidate for TB and NTM infections (CTR20192047). According to the limited experimental results from the literature, its solubility has been shown to be better than that of PMD, and its activity against MDR-Mtb strains is excellent, with an MIC of 0.03 μg·mL
−1—about one-fourth that of PMD. The preliminary PK parameters of aulimanid following IV administration at a dose of 5 mg·kg
−1 in Sprague-Dawley (SD) rats revealed a long
T1/2 (5.83 h), adequate
Cmax (987.26 ng·mL
−1), and excellent AUC
(0-24)/AUC
(0-∞) (9404.02/10003.61) for the compound. Although other publicly available preclinical or clinical study information on aulimanid is still very limited, the developer believes that it is currently among the more promising new anti-TB candidates [
99].
11. An antibacterial agent in phase-3 development with activity against Gram-negative bacilli
Benapenem is a novel carbapenem being developed by Sihuan Pharmaceutical that displays activity against ESBL-producing Enterobacteriaceae. It exhibits
in vitro activity comparable to that of ertapenem against ESBL-producing
E. coli,
K. pneumoniae, and Enterobacter cloacae strains, with an MIC
50/
90 of ≤ 0.25/≤ 0.5 μg·mL
−1. However, as a new carbapenem antibiotic targeting Gram-negative rods in late-stage clinical development, it is not or insufficiently active against critical WHO priority pathogens, due to the latter’s likely cross-resistance to market-available carbapenems. The bacteriostatic or bactericidal effects of benapenem
in vivo greatly rely on the percentage of the time that the free drug concentration remains above the MIC (%fT > MIC), and a target of %fT > MIC above 60% is recommended to ensure bactericidal efficacy [
34], [
100]. A phase-1 trial conducted in 142 healthy Chinese volunteers demonstrated that benapenem had a longer serum
T1/2 (6 to ∼7.3 h) than market-available carbapenems (1 to ∼4 h), and the subjects well tolerated ascending single doses and multiple doses of benapenem up to 1000 mg∙d
−1. Thus, the PK and safety profiles of benapenem support its once-daily dosing in clinical practice [
101]. In a study evaluating the PK characteristics of benapenem in subjects with mild-to-moderate renal impairment, it was found that patients with renal dysfunction did not need to adjust their dosage of benapenem, because their plasma drug concentrations did not significantly increase [
102]. A phase-2/-3 clinical trial (NCT04505683) has completed recruitment to assess the efficacy and safety of using IV benapenem in patients with cUTI and/or AP [
103]. In 2022, Sihuan Pharmaceutical announced the signing of an exclusive license agreement with New Asia Pharmaceutical for the development and commercialization of benapenem in the Greater China territory [
104].
12. Discussion and conclusions
In the past two decades, technological progress—coupled with government incentives and regulatory reforms—has significantly promoted China’s activities in new drug R&D [
105]. The Pharma R&D Annual Review 2022 released by Informa Pharma Intelligence, the global business intelligence provider for the biopharma industry, showed that China’s active new drug R&D pipelines (including those in the preclinical stage, those passing clinical tests and regulatory approval stages, and those drugs to be listed) accounted for about a fifth (20.8%) of the world’s total as of January 4, 2022, ranking second after the United States [
106]. In China, various national action projects have played a role in promoting and assisting the development of innovative drugs [
13]. For example, during the period of the 13th Five-Year Plan (2016-2020), the MoST focused on supporting the R&D of new antibacterial agents and techniques for the treatment of infections caused by antibiotic-resistant bacteria. A total of 12 research projects related to new antimicrobial pipelines and antibiotic resistance development were funded through the NMPID, with an investment of 201 million CNY from the central government and 408 million CNY from local governments and enterprises (approximately 100 million USD in total) [
107]. As shown in
Table 1,
Table 2 of this review, the NMPID has covered and funded the absolute majority of novel antibacterial drugs (19/20) that come to market and NDA submissions/clinical evaluations over the past three years.
Of the 17 new antibiotics currently in different clinical development stages, most have predictable therapeutic potential for infections caused by various WHO priority pathogens and/or MDR-TB; therefore, once some of them successfully receive market authorization in the future, the available antibiotic toolbox of Chinese clinicians will be well enriched to fight against infections due to antimicrobial resistance. Among the new antibacterial agents involved in this review, except for r-lysostaphin from Shanghai Hi-Tech Bioengineering, which is the only biologic agent, all the remaining antibiotics—including two recently approved new antibiotics (carrimycin and contezolid)—are small-molecule chemical entities or combinations. This fact not only reveals that small-molecule chemicals are still the main force in the current new antibacterial R&D but also indicates that there is great room for progress in the development of biotechnology-based new antibacterial treatments in China. However, the innovation of these small-molecule new antibacterial pipelines is not particularly prominent from a strict perspective, and almost all the chemical entities of these drug candidates, including two hybrid antibiotics, are derivatives of market-available antibiotics with traditionally bacteriostatic and/or bactericidal MoAs. As modified analogs of existing antibacterial drugs, once these drug candidates obtain a marketing license in the future, they will encounter fierce market competition from similar products, both internationally and domestically. In this situation, the return on investment (ROI) might be an important concern for companies engaged in these new antibiotic developments in China. In contrast to medicines used for cancers and chronic diseases such as diabetes, hypertension, and heart diseases, antibacterial drugs are typically used for short periods by patients with an episode of infection. Antibiotics are usually taken for a few days or 1-2 weeks, strictly by patients with infection indications to avoid developing antibiotic resistance, while drugs for chronic diseases are taken every day for years or a lifetime and by large numbers of people in the population. The market for antibiotics is thus much smaller and less predictable, which is why major pharmaceutical companies in developed countries such as the United States have largely abandoned investing in the market, and much of the innovation in antibiotics is undertaken by small and medium-sized enterprises (SMEs). Unfortunately, the SMEs that drive antibiotic development have a higher dependence on ROI and a poorer ability to withstand failure risks [
108]. A typical negative case is Achaogen, an SME in the United States that developed plazomicin, a novel aminoglycoside antibiotic with activity against CRE. It went bankrupt in April 2019, less than a year after the US FDA approved the antibiotic, because it was not making enough of a profit to stay afloat [
109]. Achaogen’s lesson highlights the challenge of profitability for antibiotic developers and has sparked heated discussion and reflection in the pharmaceutical industry sector in China. Although most of the Chinese companies currently engaged in the development of new antibiotics are large enterprises with good profitability, coupled with China’s large population and relatively large market size for new antibiotics, ROI remains an unavoidable issue. In the future, a subscription-based payment model for antibiotics similar to that launched by the UK government in 2020 may be a good choice for China. Through this model, pharmaceutical enterprises can obtain sufficient returns to encourage their work on much-needed new antibiotics [
110], [
111]. Of course, the planning of such an “antibiotic pull incentive” option should also take into account its affordability for patients with a demand for new antibiotics.
The pharmacophore is the key part of a molecular structure that defines a particular biological or pharmacological activity and is the basis to determine whether an antibacterial agent belongs to a new class or new subclass of antibiotics [
7]. As shown in
Fig. 3(c), among the ten clinical antibacterial pipelines with potency against the antibiotic-resistant priority pathogens, the pharmacophores are mainly concentrated in six antibiotic classes: oxazolidinones, tetracyclines, polymyxins, β-lactams, BLI, and rifamycin-antibiotic conjugates. This means that two or more of the antibiotics share the same pharmacophore. For example, both TNP-2092 and TNP-2198 are rifamycin-based antibiotic hybrids, while polymyxin E
2, MRX-8, and ASK0912 are all polymyxins. Similarly, the pharmacophores of the six anti-TB drug candidates tend to fall into limited categories, among which both oxazolidinones and nitroimidazoles have two drug candidates (TBI-223 and OTB-658; JBD0131 and aulimanid) under clinical study (
Fig. 3(d)). Interestingly, of the chemical classes identified, only oxazolidinones and bedaquilines—the most recent compounds—have been reported since 2000, while the other classes were discovered prior to the 1970s. Based on their MoAs, all antibacterial and anti-TB drugs in this review can be categorized into five major classes: protein-synthesis (oxazolidinones and tetracyclines), cell-membrane (polymyxins), cell-wall (β-lactams and BLI), DNA/RNA synthesis (rifamycin-quinolizinone hybrid), and bacterial-respiratory-system (bedaquilines, nitroimidazoles, clofazimines, and rifamycin-nitroimidazole conjugate) inhibitors, all belonging to known types of antibiotic mechanisms of action. In summary, there is still a lack of “first-in-the-world” antibacterial drugs with really innovative pharmacophore types, targets, or action modes originating in China in recent years.
Inadequate innovation may undermine the antibacterial performance and health gains from new antibacterial developments. However, discovering and developing an antibiotic acting on a novel target or with a new MoA is very challenging. Globally, only a small fraction of the antibiotics approved over the past 40 years represent novel compound classes or act through a new mechanism, while the majority have been derived from already-known chemical structures. Indeed, more than 75% of current antibacterial pipelines under clinical development in the world still belong to existing antibiotic classes [
10]. From an economic perspective, it is easy to understand why so many pharmaceutical companies—including those in China—are investing in the development of new antibiotics within known chemical classes. For one thing, the cost and risk of developing derivatives of established compound classes are much lower than those of entirely new scaffolds; for another, many antibiotic scaffolds still have considerable space for optimization to improve their efficacy, antibacterial spectrum, and safety [
112], [
113]. One successful representative of a valuable new drug within a known class is cefiderocol, developed by Shionogi & Co., Ltd., Japan, which obtained US FDA approval in 2019 for the treatment of UTI and in 2020 to include HAP/VAP. Cefiderocol is a catechol-substituted siderophore cephalosporin that chelates extracellular iron and penetrates the periplasmic space of Gram-negative bacteria via iron transporter channels in the outer membrane; it was thought to be a milestone therapeutic agent capable of combating carbapenem-resistant pathogens [
114]. The demonstration effect generated by such successful cases naturally made many companies—especially SMEs with limited financial resources or in early development stages—keen to develop new antibiotics by modifying compounds from existing chemical classes. Moreover, considering that there is still a significant gap in overall financial investment, scientific and technology accumulation, and innovation level between China and its global counterparts, particularly economies advanced in innovative antibiotic R&D, the development of new antibiotics through this approach may be a reality at present—and for a good while yet—for many pharmaceutical companies in China [
105], [
115]. The pipelines summarized in this review also reflect this likelihood somewhat.
Certainly, the antibacterial pipelines discussed herein may face some challenges and uncertainties in their further clinical development in China. An evident challenge or shortcoming of the new drugs developed by modifying existing antibiotic classes is that it is difficult for most of them to avoid cross-resistance with clinically used antibiotics today, due to their overlapping cellular targets and MoAs. Taking cefiderocol as an example once more, with its increasingly use in clinical practice in some countries, an increasing number of resistant or reduced-susceptibility isolates to the drug have been reported, especially among Gram-negative pathogens bearing β-lactamases such as MBLs, KPC-41/KPC-50, OXA-427, PER-type/SHV-type EBSLs, and AmpC variants [
116]. Another challenge or question may be the drug candidates’ probability of achieving approval from the NMPA. Due to a lack of publicly available data on the previous success rate of new drug approvals in China, it is difficult to assert how many of the 17 clinical pipelines will finally survive the rigorous process. However, according to data from the US FDA, the success rate from phase-1 trials to approval for all antibacterial therapeutics between 2011 and 2020 was only 16.3%, and the most prominent crack in the pipeline is the transition between phase-1 and phase-2 [
117]. Thus, it can be reasonably estimated that not a particularly high proportion of the drug candidates discussed here—especially those under early clinical development (in phase-1)—will be capable of successfully completing the NMPA approval process in the future. Given that safety concerns (observable in phase-1) and lack of efficacy (after stage 2) are the two most common determinants of failure for clinical candidates with disclosed discontinuation reasons, the prospects of these antibacterial pipelines developed by Chinese enterprises depend on their profiles in these two aspects during clinical evaluations. In addition, even if some of these antibacterial clinical pipelines developed by Chinese companies successfully obtain NMPA approval, they will encounter a number of commercial obstacles and challenges as late entrants into a market dominated by generics.
As is well known, the development of new and effective antibacterial drugs to treat MDR pathogens is acknowledged to be one of the most urgent health needs in the world [
118]. Over the past two decades, supporting and incentivizing antimicrobial drug development has become a governmental priority in China [
119]. Driven and encouraged by health needs and Chinese government policies, more and more enterprises in China have invested funds and intelligence into innovative antibacterial drug R&D projects. As updated in this review, a total of 17 pharmaceutical companies or organizations have been identified as the developers behind the 20 antibacterial R&D programs (
Fig. 4(a)). Among them, MicuRx, TenNor Therapeutics, and IMM/TB Alliance all have two clinical antibacterial pipelines ongoing, which to some extent reflects their relatively greater concern and investment in the programs of antibacterial therapeutics. It is worth noting that several drug candidates, such as TBI-166, TBI-223, JBD0131, polymyxin E
2, and ASK-0912, were obtained through collaborative research and development between academia and industry. In recent years, Chinese academic institutions including IMB, IMM, China State Institute of Pharmaceutical Industry (CSIPI), and Sichuan University have maintained relatively high activity in bringing novel antibiotic products to the market through industrial-academic cooperation at the early stage. In addition, by analyzing the geographical distribution of the developers and their antibacterial R&D projects involved in this review, we found that they are mainly located in provinces and cities with highly ranked economies and modernization within China, such as Jiangsu, Shanghai, Shandong, Beijing, Sichuan, Guangdong, and Liaoning. This finding can be viewed as indicating that the development of new antibiotics is costly and highly dependent on the level of pharmaceutical industrialization. Moreover, except for Sichuan, which is located in southwestern China, all other identified provinces and cities are located in the eastern coastal areas of China. (
Fig. 4(b)).
Recently, several high-quality reviews have been published that analyzed and discussed the latest progress and trends in preclinical and clinical antibacterial pipelines from a global perspective and mentioned parts of products under clinical investigation that originated in China [
5], [
6], [
7], [
8], [
9], [
10], [
120]. However, none of them specially and systematically summarized and introduced the new antibacterial pipelines originating in China. By comparative analysis, it is believed that 30% (6/20) of the new antibacterial pipelines discussed in the present review—including carrimycin, r-lysostaphin, polymyxin E
2, ASK0912, HRS-8427, and aulimanid—have never been covered by previously published reviews on similar topics. Through this review, we hope that international and domestic researchers in the pharmaceutical academia and industry will become aware of the significant advances in the R&D of new antibacterial drugs, especially those clinical pipelines with potential against drug-resistant “superbugs,” in recent years in China. Given the large population and increasingly aging society, China’s demand for new antibiotics will undoubtedly increase in the future. It is believed that, under sustained investment in antibacterial R&D, coupled with collaborative innovation between academia and industry, more real “first-in-class” antibacterial drugs will be developed in China. In order to sustain and promote developers’ interest in antibacterial R&D in the future, China can also draw on valuable experiences from developed countries. For example, we can develop further incentive measures, such as market-entry rewards that decouple revenue from sales volume for newly approved drugs, and increase funds to advance candidates under preclinical and clinical stages. At the same time, we should not forget the role of the “shield”—that is, delaying the emergence and spread of antibacterial resistance. By defining and establishing strong antimicrobial stewardship measures to reinforce infection prevention and control antibiotic misuse, we can use existing and future antibacterial drugs to treat infections more effectively and reduce the occurrence of antimicrobial resistance.
Acknowledgments
This work was supported by the National Natural Science Foundation of China (32141003 and 82330110), the CAMS Innovation Fund for Medical Sciences (CIFMS; 2021-I2M-1-039), the National Science and Technology Infrastructure of China (National Pathogen Resource Center-NPRC-32), and the Fundamental Research Funds for the Central Universities (2021-PT350-001).
Compliance with ethics guidelines
Xinyi Yang, Congran Li, Xiukun Wang, Zhonghui Zheng, Peiyi Sun, Chunjie Xu, Luni Chen, Jiandong Jiang, Staffan Normark, Birgitta Henriques-Normark, and Xuefu You declare that they have no conflict of interest or financial conflicts to disclose.
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