Targeting Plasmid Conjugation with Cinnamic Acid: A Novel Approach to Combat Antibiotic Resistance

Engineering ›› DOI: 10.1016/j.eng.2025.06.040

review-article

Gong Li ^a^,^b^,^c^,^#
, Ang Gao ^a^,^c^,^#
, Xin-Yi Lu ^a^,^c
, Tian-Hong Zhou ^a^,^c
, Shi-Ying Zhou ^a^,^c
, Li-Juan Xia ^a^,^c
, Lei Wan ^a^,^c
, Yu-Zhang He ^a^,^c
, Xin-Yi Chen ^a^,^c
, Wen-Ying Guo ^a^,^c
, Jia-Min Zheng ^a^,^c
, Hao Ren ^a^,^c
, Sheng-Qiu Tang ^b
, Xiao-Ping Liao ^a^,^c
, Liang Chen ^d^,^*
, Jian Sun ^a^,^c^,^*

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Abstract

The global spread of antibiotic resistance genes (ARGs) continues to worsen, with plasmid-mediated conjugation serving as a major transmission route. Although developing conjugation inhibitors to block this process is a promising strategy, current options are limited by toxicity and poor in vivo efficacy. This study evaluated the effect of cinnamic acid (CA; 3-phenyl-2-acrylic acid), a widely abundant food additive found in cinnamon, on plasmid conjugation. CA effectively inhibited the conjugation of various resistance plasmids in vitro, ex vivo, and in vivo. Transcriptomic analysis indicated that CA disrupts the electron transport chain (ETC) and proton motive force (PMF) by inhibiting the tricarboxylic acid (TCA) cycle, leading to reduced intracellular adenosine triphosphate (ATP)—a critical factor for plasmid conjugation. Biocompatibility assays showed that CA maintains high biosafety while preserving gut microbiota homeostasis. Therefore, these findings provide new insights into ARG inhibition and highlight the potential of CA as a novel strategy to combat the global rise in antibiotic-resistant infections.

Keywords

Conjugation / Cinnamic acid / Horizontal gene transfer / Conjugation inhibitor / Energy metabolism

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Gong Li, Ang Gao, Xin-Yi Lu, Tian-Hong Zhou, Shi-Ying Zhou, Li-Juan Xia, Lei Wan, Yu-Zhang He, Xin-Yi Chen, Wen-Ying Guo, Jia-Min Zheng, Hao Ren, Sheng-Qiu Tang, Xiao-Ping Liao, Liang Chen, Jian Sun. Targeting Plasmid Conjugation with Cinnamic Acid: A Novel Approach to Combat Antibiotic Resistance. Engineering DOI:10.1016/j.eng.2025.06.040

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References

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[1]	Prestinaci F, Pezzotti P, Pantosti A.Antimicrobial resistance: a global multifaceted phenomenon.Pathog Glob Health 2015; 109(7):309-318.

[2]	Hendriksen RS, Munk P, Njage P, van BBunnik, McNally L, Lukjancenko O, et al.Global monitoring of antimicrobial resistance based on metagenomics analyses of urban sewage.Nat Commun 2019; 10:1124.

[3]	Arias CA, Murray BE.Antibiotic-resistant bugs in the 21st century—a clinical super-challenge.N Engl J Med 2009; 360(5):439-443.

[4]	Lerminiaux NA, Cameron ADS.Horizontal transfer of antibiotic resistance genes in clinical environments.Can J Microbiol 2019; 65(1):34-44.

[5]

Yong D, Toleman MA, Giske CG, Cho HS, Sundman K, Lee K, et al.Characterization of a new Metallo-β-Lactamase gene, bla_NDM-1, and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India.Antimicrob Agents Chemother 2009; 53(12):5046-5054.

[6]	Liu Y, Wang Y, Walsh TR, Yi LX, Zhang R, Spencer J, et al.Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study.Lancet Infect Dis 2016; 16(2):161-168.

[7]	He T, Wang R, Liu D, Walsh TR, Zhang R, Lv Y, et al.Emergence of plasmid-mediated high-level tigecycline resistance genes in animals and humans.Nat Microbiol 2019; 4(9):1450-1456.

[8]	Sun J, Chen C, Cui C, Zhang Y, Liu X, Cui Z, et al.Plasmid-encoded tet(X) genes that confer high-level tigecycline resistance in Escherichia coli.Nat Microbiol 2019; 4(9):1457-1464.

[9]	Liu YY, Lu L, Yue C, Gao X, Chen J, Gao G, et al.Emergence of plasmid-mediated high-level tigecycline resistance gene tet(X4) in Enterobacterales from retail aquatic products.Food Res Int 2024; 178:113952.

[10]	Li Y, Xu L, Li Y, Wang M, He T, Bai L, et al.Genomic and functional analysis of high-level tigecycline resistant Klebsiella michiganensis co-carrying tet(X4) and tmexCD2-toprJ2 from pork.Int J Food Microbiol 2023; 391:110138.

[11]	Van W Schaik, Händel N, Otte S, Jonker M, Brul S, ter BHKuile.Factors that affect transfer of the IncI1 β-lactam resistance plasmid pESBL-283 between E. coli strains.PLoS One 2015; 10(4):e0123039.

[12]	McInnes RS, McCallum GE, Lamberte LE, van WSchaik.Horizontal transfer of antibiotic resistance genes in the human gut microbiome.Curr Opin Microbiol 2020; 53:35-43.

[13]	Liu W, Huang Y, Zhang H, Liu Z, Huan Q, Xiao X, et al.Factors and mechanisms influencing conjugation in vivo in the gastrointestinal tract environment: a review.Int J Mol Sci 2023; 24(6):5919.

[14]	Wang H, Qi H, Zhu M, Gong S, Huang Z, Zhang Y, et al.MoS₂ decorated nanocomposite: Fe₂O₃@MoS₂ inhibits the conjugative transfer of antibiotic resistance genes.Ecotoxicol Environ Saf 2019; 186:109781.

[15]	Kwapong AA, Stapleton P, Gibbons S.Inhibiting plasmid mobility: the effect of isothiocyanates on bacterial conjugation.Int J Antimicrob Agents 2019; 53(5):629-636.

[16]	Alav I, Pordelkhaki P, de PEResende, Partington H, Gibbons S, Lord RM, et al.Cobalt complexes modulate plasmid conjugation in Escherichia coli and Klebsiella pneumoniae.Sci Rep 2024; 14(1):8103.

[17]	Buckner MMC, Ciusa ML, Piddock LJV.Strategies to combat antimicrobial resistance: anti-plasmid and plasmid curing.FEMS Microbiol Rev 2018; 42(6):781-804.

[18]	Getino M, de Fla Cruz.Natural and artificial strategies to control the conjugative transmission of plasmids.Microbiol Spectr 2018; 6(1):MTBP-0015-2016.

[19]	Adisakwattana S.Cinnamic acid and its derivatives: mechanisms for prevention and management of diabetes and its complications.Nutrients 2017; 9(2):163.

[20]	Ruwizhi N, Aderibigbe BA.Cinnamic acid derivatives and their biological efficacy.Int J Mol Sci 2020; 21(16):5712.

[21]	Radtke J, Linseisen J, Wolfram G.Phenolic acid intake of adults in a Bavarian subgroup of the national food consumption survey.Z Ernährungswiss 1998; 37(2):190-197.

[22]	P Jérez-Jiménez, Fezeu L, Touvier M, Arnault N, Manach C, Hercberg S, et al.Dietary intake of 337 polyphenols in French adults.Am J Clin Nutr 2011; 93(6):1220-1228.

[23]	Li H, Ma Y, Gao X, Chen G, Wang Z.Probing the structure-antioxidant activity relationships of four cinnamic acids porous starch esters.Carbohydr Polym 2021; 256:117428.

[24]	Alam MA, Subhan N, Hossain H, Hossain M, Reza HM, Rahman MM, et al.Hydroxycinnamic acid derivatives: a potential class of natural compounds for the management of lipid metabolism and obesity.Nutr Metab 2016; 13:27.

[25]	Nguyen TV, Nguyen TMH, Ha TT, Nguyen TD, Bui DH.Antiplatelet and anticoagulant effects of two new phenylpropanoid sucrose esters and other secondary metabolites from the aerial part of Canna edulis.Chem Biodivers 2024; 21(5):e202400302.

[26]	Li G, Long TF, Zhou SY, Xia LJ, Gao A, Wan L, et al.CRISPR-AMRtracker: a novel toolkit to monitor the antimicrobial resistance gene transfer in fecal microbiota.Drug Resist Updat 2024; 77:101142.

[27]	Zhang P, Mao D, Gao H, Zheng L, Chen Z, Gao Y, et al.Colonization of gut microbiota by plasmid-carrying bacteria is facilitated by evolutionary adaptation to antibiotic treatment.ISME J 2022; 16(5):1284-1293.

[28]	Zhang Y, Li W, Wu Y, Tian X, Li G, Zhou Y, et al.Chitosan oligosaccharide accelerates the dissemination of antibiotic resistance genes through promoting conjugative plasmid transfer.J Hazard Mater 2024; 469:133922.

[29]	Bolyen E, Rideout JR, Dillon MR, Bokulich NA, Abnet CC, Al-Ghalith GA, et al.Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2.Nat Biotechnol 2019; 37(8):852-857.

[30]	Quast C, Pruesse E, Yilmaz P, Gerken J, Schweer T, Yarza P, et al.The SILVA ribosomal RNA gene database project: improved data processing and web-based tools.Nucleic Acids Res 2012; 41(D1):D590-D596.

[31]	Li G, Han L, Xia L, Gao A, Li Z, Zhou S, et al.Waterborne polyurethane nanoparticles incorporating linoleic acid as a potential strategy for controlling antibiotic resistance spread in the mammalian intestine.Mater Today Bio 2024; 28:101181.

[32]	Yang B, Wang Z, Jia Y, Fang D, Li R, Liu Y.Paclitaxel and its derivative facilitate the transmission of plasmid-mediated antibiotic resistance genes through conjugative transfer.Sci Total Environ 2022; 810:152245.

[33]	Kim D, Landmead B, Salzberg SL.HISAT: a fast spliced aligner with low memory requirements.Nat Methods 2015; 12(4):357-U121.

[34]	Wang X, Song H, Yi T, Shen Y, Dai C, Sun C, et al.Dihydroartemisinin inhibits plasmid transfer in drug-resistant Escherichia coli via limiting energy supply.Zool Res 2023; 44(5):894-904.

[35]	Zhu S, Yang B, Jia Y, Yu F, Wang Z, Liu Y.Comprehensive analysis of disinfectants on the horizontal transfer of antibiotic resistance genes.J Hazard Mater 2023; 453:453.

[36]	Fu Q, Li S, Wang Z, Shan W, Ma J, Cheng Y, et al.H-NS mutation-mediated CRISPR-Cas activation inhibits phage release and toxin production of Escherichia coli Stx2 phage lysogen.Front Microbiol 2017; 8:652.

[37]	Datta N, Hedges RW.Compatibility groups among fi⁻ R factors.Nature 1971; 234(5326):222-223.

[38]	Mead A, Billon-Lotz C, Olsen R, Swift B, Richez P, Stabler R, et al.Epidemiological prevalence of phenotypical resistances and mobilised colistin resistance in avian commensal and pathogenic E. coli from Denmark, France, the Netherlands, and the UK.Antibiotics 2022; 11(5):631.

[39]	Zhou Y, Yang Y, Li X, Tian D, Ai W, Wang W, et al.Exploiting a conjugative endogenous CRISPR-Cas3 system to tackle multidrug-resistant Klebsiella pneumoniae.EBioMedicine 2023; 88:104445.

[40]	Xiao X, Zeng F, Li R, Liu Y, Wang Z.Subinhibitory concentration of colistin promotes the conjugation frequencies of mcr-1- and bla_NDM-5-positive plasmids. Microbiol Spectr, 10 (2) (2022)

[41]	Li G, Xia L, Zhou S, Wang X, Cui C, He Y, et al.Linoleic acid and α-linolenic acid inhibit conjugative transfer of an IncX4 plasmid carrying mcr-1.J Appl Microbiol 2021; 130(6):1893-1901.

[42]	Lu J, Wang Y, Li J, Mao L, Nguyen SH, Duarte T, et al.Triclosan at environmentally relevant concentrations promotes horizontal transfer of multidrug resistance genes within and across bacterial genera.Environ Int 2018; 121:1217-1226.

[43]	Stecher B, Denzler R, Maier L, Bernet F, Sanders MJ, Pickard DJ, et al.Gut inflammation can boost horizontal gene transfer between pathogenic and commensal Enterobacteriaceae.Proc Natl Acad Sci USA 2012; 109(4):1269-1274.

[44]	Yang QE, Ma X, Zeng L, Wang Q, Li M, Teng L, et al.Interphylum dissemination of NDM-5-positive plasmids in hospital wastewater from Fuzhou, China: a single-centre, culture-independent, plasmid transmission study.Lancet Microbe 2024; 5(1):13-23.

[45]	Ruskoski SA, McDonald AA, Bleichner JJ, Aga SS, Boyina K, Champlin FR.Disparate properties of Burkholderia multivorans and Pseudomonas aeruginosa regarding outer membrane chemical permeabilization to the hydrophobic substances novobiocin and triclosan.PLoS One 2023; 18(4):e0284855.

[46]	Lu J, Wang Y, Zhang S, Bond P, Yuan Z, Guo J.Triclosan at environmental concentrations can enhance the spread of extracellular antibiotic resistance genes through transformation.Sci Total Environ 2020; 713:136621.

[47]	Musovic S, Dechesne A, S Jørensen, Smets BF.Novel assay to assess permissiveness of a soil microbial community toward receipt of mobile genetic elements.Appl Environ Microbiol 2010; 76(14):4813-4818.

[48]	Soda S, Otsuki H, Inoue D, Tsutsui H, Sei K, Ike M.Transfer of antibiotic multiresistant plasmid RP4 from Escherichia coli to activated sludge bacteria.J Biosci Bioeng 2008; 106(3):292-296.

[49]	Sher AA.Transmission of antibiotic resistance genes encoded on a broad host range RP4 plasmid among members of the human gut microbiota [dissertation]. Michigan State University, East Lansing (2022)

[50]	Wang Y, Yu Z, Ding P, Lu J, Kluemper U, Murray AK, et al.Non-antibiotic pharmaceuticals promote conjugative plasmid transfer at a community-wide level.Microbiome 2022; 10(1):124.

[51]	Yu Z, Henderson IR, Guo J.Non-caloric artificial sweeteners modulate conjugative transfer of multi-drug resistance plasmid in the gut microbiota.Gut Microbes 2023; 15(1):2157698.

[52]	Neil K, Allard N, Grenier F, Burrus V, Rodrigue S.Highly efficient gene transfer in the mouse gut microbiota is enabled by the Incl2 conjugative plasmid TP114.Commun Biol 2020; 3(1):523.

[53]	Bird CD, Emery NJ.Insightful problem solving and creative tool modification by captive nontool-using rooks.Proc Natl Acad Sci USA 2009; 106(25):10370-10375.

[54]	Liu Y, Shi C, Ming P, Yuan L, Jiang X, Jiang M, et al.Biomimetic fabrication of sr-silk fibroin co-assembly hydroxyapatite based microspheres with angiogenic and osteogenic properties for bone tissue engineering.Mater Today Bio 2024; 25:101011.

[55]	Zhao C, Li J, Li C, Xue B, Wang S, Zhang X, et al.Horizontal transfer of the multidrug resistance plasmid RP4 inhibits ammonia nitrogen removal dominated by ammonia-oxidizing bacteria.Water Res 2022; 217:118434.

[56]	Zhu L, Chen T, Xu L, Zhou Z, Feng W, Liu Y, et al.Effect and mechanism of quorum sensing on horizontal transfer of multidrug plasmid RP4 in BAC biofilm.Sci Total Environ 2020; 698:134236.

[57]	Hess S, Kneis D, Virta M, Hiltunen T.The spread of the plasmid RP4 in a synthetic bacterial community is dependent on the particular donor strain.FEMS Microbiol Ecol 2021; 97(12):fiab147.

[58]	Song H, Wang X, Zhang M, Zou Z, Yang S, Yi T, et al.Dual effects of feed-additive-derived chelerythrine in combating mobile colistin resistance.Engineering 2024; 32:163-173.

[59]	Qiu Y, Zhang J, Li B, Wen X, Liang P, Huang X.A novel microfluidic system enables visualization and analysis of antibiotic resistance gene transfer to activated sludge bacteria in biofilm.Sci Total Environ 2018; 642:582-590.

[60]	Confer AW, Ayalew S.The OmpA family of proteins: roles in bacterial pathogenesis and immunity.Vet Microbiol 2013; 163(3–4):207-222.

[61]	Khalid S, Bond PJ, Carpenter T, Sansom MSP.OmpA: gating and dynamics via molecular dynamics simulations.Biochim Biophys Acta Biomembr 2008; 1778(9):1871-1880.

[62]	Lin X, Zhang C, Han R, Li S, Peng H, Zhou X, et al.Oxytetracycline and heavy metals promote the migration of resistance genes in the intestinal microbiome by plasmid transfer.ISME J 2023; 17(11):2003-2013.

[63]	Zhang S, Wang Y, Lu J, Yu ZG, Song HL, Bond PL, et al.Chlorine disinfection facilitates natural transformation through ROS-mediated oxidative stress.ISME J 2021; 15(10):2969-2985.

[64]	Zhang S, Wang Y, Song H, Lu J, Yuan Z, Guo J.Copper nanoparticles and copper ions promote horizontal transfer of plasmid-mediated multi-antibiotic resistance genes across bacterial genera.Environ Int 2019; 129:478-487.

[65]	Cen T, Zhang X, Xie S, Li D.Preservatives accelerate the horizontal transfer of plasmid-mediated antimicrobial resistance genes via differential mechanisms.Environ Int 2020; 138:105544.

[66]	Delcour AH.Outer membrane permeability and antibiotic resistance.Biochim Biophys Acta 2009; 1794(5):808-816.

[67]	Knopp M, Andersson DI.Amelioration of the fitness costs of antibiotic resistance due to reduced outer membrane permeability by upregulation of alternative porins.Mol Biol Evol 2015; 32(12):3252-3263.

[68]	Song M, Liu Y, Huang X, Ding S, Wang Y, Shen J, et al.A broad-spectrum antibiotic adjuvant reverses multidrug-resistant Gram-negative pathogens.Nat Microbiol 2020; 5(8):1040-1050.

[69]	Schröder G, Lanka E.The mating pair formation system of conjugative plasmids-a versatile secretion machinery for transfer of proteins and DNA.Plasmid 2005; 54(1):1-25.

[70]	Pansegrau W, Balzer D, Kruft V, Lurz R, Lanka E.In vitro assembly of relaxosomes at the transfer origin of plasmid RP4.Proc Natl Acad Sci USA 1990; 87(17):6555-6559.

[71]	Gubbins MJ, Lau I, Will WR, Manchak JM, Raivio TL, Frost LS.The positive regulator, Traj, of the Escherichia coli F plasmid is unstable in a cpxA* background.J Bacteriol 2002; 184(20):5781-5788.

[72]	Wang K, Zheng X, Zhang X, Zhao L, Yang Q, Boateng NAS, et al.Comparative transcriptomic analysis of the interaction between Penicillium expansum and apple fruit (Malus pumila Mill.) during early stages of infection.Microorganisms 2019; 7(11):495.

[73]	Huang H, Feng G, Wang M, Liu C, Wu Y, Dong L, et al.Nitric oxide: a neglected driver for the conjugative transfer of antibiotic resistance genes among wastewater microbiota.Environ Sci Technol 2022; 56(10):6466-6478.

[74]	Katayama N, Iwazumi K, Suzuki H, Osanai T, Ito S.Malic enzyme, not malate dehydrogenase, mainly oxidizes malate that originates from the tricarboxylic acid cycle in cyanobacteria.MBio 2022; 13(6):e0218722.

[75]	MacLean A, Legendre F, Appanna VD.The tricarboxylic acid (TCA) cycle: a malleable metabolic network to counter cellular stress.Crit Rev Biochem Mol Biol 2023; 58(1):81-97.

[76]	Meyrat A, von CBallmoos.ATP synthesis at physiological nucleotide concentrations.Sci Rep 2019; 9:3070.

[77]	Jia Y, Yang B, Shi J, Fang D, Wang Z, Liu Y.Melatonin prevents conjugative transfer of plasmid-mediated antibiotic resistance genes by disrupting proton motive force.Pharmacol Res 2022; 175:105978.

[78]	Kubori T.A two-component system serves as a central hub for connecting energy metabolism and plasmid dissemination in bacteria.MBio 2023; 14(6):e0247423.

[79]	Wu Y, Yan H, Zhu X, Liu C, Chu C, Zhu X, et al.Biochar effectively inhibits the horizontal transfer of antibiotic resistance genes via restraining the energy supply for conjugative plasmid transfer.Environ Sci Technol 2022; 56(17):12573-12583.

[80]	Peng ZS, Wang LD, Guan QT, Chu X, Luo ZQ.Acinetobacter baumannii coordinates central metabolism, plasmid dissemination, and virulence by sensing nutrient availability. MBio, 14 (6) (2023)

[81]	Zhang M, Yang B, Shi J, Wang Z, Liu Y.Host defense peptides mitigate the spread of antibiotic resistance in physiologically relevant condition.Antimicrob Agents Chemother 2024; 68(4):e0126123.

[82]	Casu B, Arya T, Bessette B, Baron C.Fragment-based screening identifies novel targets for inhibitors of conjugative transfer of antimicrobial resistance by plasmid pKM101.Sci Rep 2017; 7:14907.

[83]	Domenech A, Brochado AR, Sender V, Hentrich K, Henriques-Normark B, Typas A, et al.Proton motive force disruptors block bacterial competence and horizontal gene transfer.Cell Host Microbe 2020; 27(4):544-555.e543.

[84]	Zhao X, Jin Y, Bai F, Cheng Z, Wu W, Pan X.Pseudomonas aeruginosa phosphate transporter PitA (PA4292) controls susceptibility to aminoglycoside antibiotics by regulating the proton motive force.Antimicrob Agents Chemother 2022; 66(12):e0099222.

[85]	Getino M, Fernandez-Lopez R, Palencia-Gandara C, Campos-Gomez J, Sanchez-Lopez JM, Martinez M, et al.Tanzawaic acids, a chemically novel set of bacterial conjugation inhibitors.PLoS One 2016; 11(1):e0148098.

[86]	Ren H, Pan Y, Zhong J, Wang J, Lu Z, He Q, et al.An antibiotic-destructase-activated Fenton-like catalyst for synergistic removal of tetracycline residues from aquatic environment.Chem Eng J 2023; 459:141576.

[87]	Tramontano M, Andrejev S, Pruteanu M, Klünemann M, Kuhn M, Galardini M, et al.Nutritional preferences of human gut bacteria reveal their metabolic idiosyncrasies.Nat Microbiol 2018; 3(4):514-522.

[88]	He Z, Ma Y, Yang S, Zhang S, Liu S, Xiao J, et al.Gut microbiota-derived ursodeoxycholic acid from neonatal dairy calves improves intestinal homeostasis and colitis to attenuate extended-spectrum β-lactamase-producing enteroaggregative Escherichia coli infection.Microbiome 2022; 10(1):79.

[89]	Lee AG, Kang S, Im S, Pak YK.Cinnamic acid attenuates peripheral and hypothalamic inflammation in high-fat diet-induced obese mice.Pharmaceutics 2022; 14(8):1675.

[90]	Liu Y, Zhao B, He P, Wang Z, Tang K, Mou Z, et al.Cinnamic acid: a low-toxicity natural bidentate ligand for uranium decorporation.Inorg Chem 2024; 63(16):7464-7472.

[91]	Guo S, Zhen Y, Zhu Z, Zhou G, Zheng X.Cinnamic acid rescues behavioral deficits in a mouse model of traumatic brain injury by targeting miR-455-3p/HDAC2.Life Sci 2019; 235:116819.

[92]	Liang C, Wan T, Wu R, Zhao M, Zhao Y, Cai Y.Resistance analysis of cherry rootstock ‘CDR-1’ (Prunus mahaleb) to crown gall disease.BMC Plant Biol 2020; 20(1):516.