根皮素通过靶向多聚磷酸激酶1降低鲍曼不动杆菌体内外毒力和持留性

吕红发; 李淑芳; 关键; 张鹏; 孔令聪; 马红霞; 李丹; 邓旭明; 牛效迪; 王建锋

doi:10.1016/j.eng.2024.09.002

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工程（英文） ›› 2024, Vol. 43 ›› Issue (12) : 258-271. DOI: 10.1016/j.eng.2024.09.002

研究论文

Article

根皮素通过靶向多聚磷酸激酶1降低鲍曼不动杆菌体内外毒力和持留性

吕红发 ^a^,¹ ,
李淑芳 ^a^,¹ ,
关键 ^a ,
张鹏 ^d ,
孔令聪 ^c ,
马红霞 ^c ,
李丹 ^e ,
邓旭明 ^a ,
牛效迪 ^b ,
王建锋 ^a

作者信息 +

Phloretin Targets Polyphosphate Kinase 1 to Attenuate Acinetobacter baumannii Virulence and Persistence In Vitro and In Vivo

Hongfa Lv ^a^,¹^,^# ,
Shufang Li ^a^,¹^,^# ,
Jian Guan ^a ,
Peng Zhang ^d ,
Lingcong Kong ^c ,
Hongxia Ma ^c ,
Dan Li ^e ,
Xuming Deng ^a ,
Xiaodi Niu ^b^,^* ,
Jianfeng Wang ^a^,^*

Author information +

History +

摘要

鲍曼不动杆菌因其毒力和持留性常造成严重性感染，特别是在医院的重症监护病房中。随着耐药菌的出现，如今迫切需要开发抗鲍曼不动杆菌感染的新策略和候选化合物。多聚磷酸盐激酶1（PPK1）参与维持细菌抗生素耐药性或耐受性、致病力和逆境生存，是细菌逆境生存所必需的。本研究通过鲍曼不动杆菌毒力和持久性相关的多项表型试验分析，发现根皮素能通过抑制PPK1活性降低鲍曼不动杆菌的毒力和持留性。根皮素降低其滑行运动能力，抑制生物被膜的形成，降低其对氨苄青霉素刺激、热刺激和过氧化氢刺激的抗性。分子模拟和定点突变试验显示，根皮素与PPK1的结合位点是ARG-22、MET-622、ASN57和ARG-65。同时，根皮素处理导致鲍曼不动杆菌的毒力和持留性相关代谢途径发生变化，包括甘油磷脂代谢和脂肪酸生物合成。此外，在小鼠肺炎感染模型中，根皮素能降低鲍曼不动杆菌在肺部的菌载量以缓解小鼠肺炎损伤。这表明具有较高应用前景的根皮素能靶向PPK1抗鲍曼不动杆菌感染。

Abstract

Acinetobacter baumannii (A. baumannii) is well known for its virulence and persistence, particularly in intensive care units. Therefore, new strategies and candidates to treat A. baumannii infection are urgently needed considering the emergence of drug-resistant bacteria. Polyphosphate kinase 1 (PPK1) is required for bacterial survival as it is involved in maintaining antibiotic resistance or tolerance, pathogenesis, and adversity resistance. Multiple phenotypic assays related to virulence and persistence were performed in this study, and phloretin was shown to attenuate A. baumannii virulence and persistence by inhibiting PPK1 activity. Phloretin hampered mobility, interfered with biofilm formation and decreased resistance to ampicillin, heat, and hydrogen peroxide stress in A. baumannii. The therapeutic effect was also examined in a mouse pneumonia infection model. Molecular simulation and site-directed mutagenesis revealed that ARG-22, MET-622, ASN-57, and ARG-65 were the sites of phloretin action against PPK1. Phloretin treatment led to changes in metabolic pathways associated with A. baumannii virulence and persistence, including glycerophospholipid metabolism and fatty acid biosynthesis. Furthermore, phloretin alleviated pneumonic injury in a mouse pneumonia infection model in vivo, indicating that phloretin is a promising compound for preventing A. baumannii infection resistance by targeting PPK1.

Keywords

Acinetobacter baumannii / Virulence / Persistence / Phloretin / Polyphosphate kinase

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吕红发, 李淑芳, 关键. 根皮素通过靶向多聚磷酸激酶1降低鲍曼不动杆菌体内外毒力和持留性. Engineering. 2024, 43(12): 258-271 https://doi.org/10.1016/j.eng.2024.09.002

参考文献

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[1]	M.E. Falagas, E.A. Karveli, I. Kelesidis, T. Kelesidis. Community-acquired Acinetobacter infections. Eur J Clin Microbiol Infect Dis, 26 (12) (2007), pp. 857-868.
[2]	W.N. Chang, C.H. Lu, C.R. Huang, Y.C. Chuang. Community-acquired Acinetobacter meningitis in adults. Infection, 28 (2000), pp. 395-397.
[3]	M.E. Falagas, P.I. Rafailidis. Attributable mortality of Acinetobacter baumannii: no longer a controversial issue. Crit Care, 11 (2007), p. 134.
[4]	A. Di Popolo, M. Giannouli, M. Triassi, S. Brisse, R. Zarrilli. Molecular epidemiological investigation of multidrug-resistant Acinetobacter baumannii strains in four mediterranean countries with a multilocus sequence typing scheme. Clin Microbiol Infec, 17 (2) (2011), pp. 190-203.
[5]	S. Pournaras, K. Dafopoulou, M. Del Franco, O. Zarkotou, E. Dimitroulia, E. Protonotariou, et al. Predominance of international clone 2 oxa-23-producing-Acinetobacter baumannii clinical isolates in Greece, 2015: results of a nationwide study. Int J Antimicrob Agents, 49 (6) (2017), pp. 749-753.
[6]	B.A. Eijkelkamp, U.H. Stroeher, K.A. Hassan, L.D.H. Elbourne, I.T. Paulsen, M.H. Brown. H-NS plays a role in expression of Acinetobacter baumannii virulence features. Infect Immun, 81 (7) (2013), pp. 2574-2583.
[7]	M.G. Thompson, C.C. Black, R.L. Pavlicek, C.L. Honnold, M.C. Wise, Y.A. Alamneh, et al. Validation of a novel murine wound model of Acinetobacter baumannii infection. Antimicrob Agents Chemother, 58 (3) (2014), pp. 1332-1342.
[8]	I. Roca, P. Espinal, X. Vila-Farrés, J. Vila. The Acinetobacter baumannii oxymoron: commensal hospital dweller turned pan-drug-resistant menace. Front Microbiol, 3 (2012), p. 148.
[9]	L.C. Antunes, F. Imperi, A. Carattoli, P. Visca. Deciphering the multifactorial nature of Acinetobacter baumannii pathogenicity. PLoS One, 6 (8) (2011), p. e22674.
[10]	M.S. Wright, S. Mountain, K. Beeri, M.D. Adams. Assessment of insertion sequence mobilization as an adaptive response to oxidative stress in Acinetobacter baumannii using IS-seq. J Bacteriol, 199 (9) (2017), pp. e00833-e916.
[11]	K.A. Hassan, S.M. Jackson, A. Penesyan, S.G. Patching, S.G. Tetu, B.A. Eijkelkamp, et al. Transcriptomic and biochemical analyses identify a family of chlorhexidine efflux proteins. Proc Natl Acad Sci USA, 110 (50) (2013), pp. 20254-20259.
[12]	M.Q. Bowlin, M.J. Gray. Inorganic polyphosphate in host and microbe biology. Trends Microbiol, 29 (11) (2021), pp. 1013-1023.
[13]	H. Zhang, K. Ishige. A polyphosphate kinase (PPK2) widely conserved in bacteria. Proc Natl Acad Sci USA, 99 (26) (2000), pp. 16678-16683.
[14]	L.K. Gautam, P. Sharma, N. Capalash. Bacterial polyphosphate kinases revisited: role in pathogenesis and therapeutic potential. Curr Drug Targets, 20 (3) (2019), pp. 292-301.
[15]	L.K. Gautam, P. Sharma, N. Capalash. Attenuation of Acinetobacter baumannii virulence by inhibition of polyphosphate kinase 1 with repurposed drugs. Microbiol Res, 242 (2021), Article 126627.
[16]	H. Lv, Y. Zhou, B. Liu, J. Guan, P. Zhang, X. Deng, et al. Polyphosphate kinase is required for the processes of virulence and persistence in Acinetobacter baumannii. Microbiol Spectr, 10 (4) (2022), Article e0123022.
[17]	J.U. Dahl, M.J. Gray, D. Bazopoulou, F. Beaufay, J. Lempart, M.J. Koenigsknecht, et al. The anti-inflammatory drug mesalamine targets bacterial polyphosphate accumulation. Nat Microbiol, 2 (2017), p. 16267.
[18]	A.G. Acosta-Cortés, C. Martinez-Ledezma, U.J. López-Chuken, G. Kaushik, S. Nimesh, J.F. Villarreal-Chiu. Polyphosphate recovery by a native Bacillus cereus strain as a direct effect of glyphosate uptake. ISME J, 13 (6) (2019), pp. 1497-1505.
[19]	J. Corral, M. Pérez-Varela, M. Sánchez-Osuna, P. Cortés, J. Barbé, J. Aranda. Importance of twitching and surface-associated motility in the virulence of Acinetobacter baumannii. Virulence, 12 (1) (2021), pp. 2201-2213.
[20]	R. Chen, R. Lv, L. Xiao, M. Wang, Z. Du, Y. Tan, et al. A1S_2811, a CheA/Y-like hybrid two-component regulator from Acinetobacter baumannii ATCC17978, is involved in surface motility and biofilm formation in this bacterium. Microbiologyopen, 6 (5) (2017), p. e00510.
[21]	A. Papadopoulou, R.J. Green, R.A. Frazier. Interaction of flavonoids with bovine serum albumin: a fluorescence quenching study. J Agric Food Chem, 53 (1) (2005), pp. 158-163.
[22]	A. Micsonai, F. Wien, É. Bulyáki, J. Kun, É. Moussong, Y.H. Lee, et al. BeStSel: a web server for accurate protein secondary structure prediction and fold recognition from the circular dichroism spectra. Nucleic Acids Res, 46 (W1) (2018), pp. W315-W322.
[23]	S. Liang, T. Wu, Y. Li, D. Liu, J. Sun, W. Bai. Study on the mechanism of interaction between mulberry anthocyanins and yeast mannoprotein. Food Chem, 405 (Pt B) ( 2023), Article 135024.
[24]	C.M. Harding, S.W. Hennon, M.F. Feldman. Uncovering the mechanisms of Acinetobacter baumannii virulence. Nat Rev Microbiol, 16 (2) (2018), pp. 91-102.
[25]	N. Roberge, N. Neville, K. Douchant, C. Noordhof, N. Boev, C. Sjaarda, et al. Broad-spectrum inhibitor of bacterial polyphosphate homeostasis attenuates virulence factors and helps reveal novel physiology of Klebsiella pneumoniae and Acinetobacter baumannii. Front Microbiol, 12 (2021), Article 764733.
[26]	T. Kondakova, F. D’Heygère, M.J. Feuilloley, N. Orange, H.J. Heipieper, P.C. Duclairoir. Glycerophospholipid synthesis and functions in Pseudomonas. Chem Phys Lipids, 190 (2015), pp. 27-42.
[27]	H. Li, Y. Wang, Q. Meng, Y. Wang, G. Xia, X. Xia, et al. Comprehensive proteomic and metabolomic profiling of mcr-1-mediated colistin resistance in Escherichia coli. Int J Antimicrob Agents, 53 (6) (2019), pp. 795-804.
[28]	X. Liu, L. Wang, T. Choera, X. Fang, G. Wang, W. Chen, et al. Paralogous FgIDO genes with differential roles in tryptophan catabolism, fungal development and virulence in Fusarium graminearum. Microbiol Res, 272 (2023), Article 127382.
[29]	B. Cui, X. Chen, Q. Guo, S. Song, M. Wang, J. Liu, et al. The cell-cell communication signal indole controls the physiology and interspecies communication of Acinetobacter baumannii. Microbiol Spectr, 10 (4) (2022), Article e0102722.
[30]	N. Neville, N. Roberge, X. Ji, P. Stephen, J.L. Lu, Z. Jia. A dual-specificity inhibitor targets polyphosphate kinase 1 and 2 enzymes to attenuate virulence of Pseudomonas aeruginosa. Bio, 12 (3) (2021), Article e0059221.