应对细菌耐药策略研究进展

doi:10.16431/j.cnki.1671-7236.2023.11.025

摘要/Abstract

摘要： 细菌耐药性与畜牧产业发展、人类公共卫生安全和食品安全密切相关。细菌产生耐药的机制复杂，除由人-动物-环境三者之间复杂作用引起外，抗生素的使用对细菌耐药性的产生和传播具有非常重要的影响，需要采取多种策略应对细菌耐药性的产生。新发展的药物理论及分子生物学等技术的兴起，极大地推动了对细菌耐药机制的认识、新型抗菌药物的发现及药物的合理使用，为控制细菌耐药性的产生提供了重要的理论依据和技术手段。当前，细菌耐药性已然是不可忽视的严重问题，引起了多方关注。细菌耐药机制的复杂性及新药研发的困难性，决定了必须通过多种方法、多种途径和多种角度开展研究，从而控制其进一步发展。基于目前的研究现状，笔者归纳总结了多种应对细菌耐药的策略及方法，重点从新型抗菌药的研发、联合用药、药代动力学-药效动力学同步模型及多组学技术等方面阐述其在应对细菌耐药性方面的作用，以期为减缓和控制细菌耐药性的产生及临床治疗细菌感染提供参考和指导。

关键词: 细菌耐药性; 多重耐药; 防控策略

Abstract: Bacteria resistance is closely related with the development of animal husbandry industry, human public health safety and food safety.The mechanism of bacteria resistance is complex.In addition to the complex interaction among human, animal and environment, the use of antibiotics has played a very important impact on the generation and spread of bacterial resistance.Therefore, it is necessary to develop a variety of strategies to cope with bacterial resistance.The newly developed drug theory and the rise of molecular biology technology have greatly promoted the understanding of bacterial drug resistance mechanism, the discovery of new antibacterial drugs and the rational use of drugs, which provided important theoretical basis and technical means for the control of bacterial drug resistance.Presently, bacterial drug resistance has been a serious problem which can not be ignored and has arouse much concern.Due to the complexity of bacterial drug resistance mechanism and the difficulty of new drug development, it is necessary to carry out research through multiple methods, approaches and perspectives to prevent further development of bacterial resistance.Based on the current research, the author summarized a variety of strategies and methods to deal with bacterial drug resistance, focusing on the development of new antimicrobial drugs, drug combination, pharmacokinetic-pharmacodynamic modelling and multi-omics technology to elaborate their role in dealing with bacterial drug resistance, which would provide reference and guidance for slowing and controlling the development of bacterial resistance and clinical treatment of bacterial infection.

Key words: bacterial resistance; multidrug resistance; control strategies

中图分类号:

S859.7

李亚菲, 张秀凤, 张灵璇, 魏彦哲, 万凯, 曾振灵. 应对细菌耐药策略研究进展[J]. 中国畜牧兽医, 2023, 50(11): 4568-4576.

LI Yafei, ZHANG Xiufeng, ZHANG Lingxuan, WEI Yanzhe, WAN Kai, ZENG Zhenling. Research Progress on Strategies to Control Bacterial Resistance: A Review[J]. China Animal Husbandry and Veterinary Medicine, 2023, 50(11): 4568-4576.

参考文献

[1] JIAN Z, ZENG L, XU T, et al.Antibiotic resistance genes in bacteria:Occurrence, spread, and control[J].Journal of Basic Microbiology, 2021, 61(12):1049-1070.
[2] SCHMID A, WOLFENSBERGER A, NEMETH J, et al.Monotherapy versus combination therapy for multidrug-resistant Gram-negative infections:Systematic review and Meta-analysis[J].Scientific Reports, 2019, 9(1):15290.
[3] VARMA G Y N, KUMMARI G, PAIK P, et al.Celecoxib potentiates antibiotic uptake by altering membrane potential and permeability in Staphylococcus aureus[J].Journal of Antimicrobial Chemotherapy, 2019, 74(12):3462-3472.
[4] SU J C, HUANG Y T, CHEN C S, et al.Design and synthesis of malonamide derivatives as antibiotics against methicillin-resistant Staphylococcus aureus[J].Molecules, 2018, 23(1):27.
[5] KIM W, ZHU W, HENDRICKS G L, et al.A new class of synthetic retinoid antibiotics effective against bacterial persisters[J].Nature, 2018, 556(7699):103-107.
[6] CHIN W, ZHONG G, PU Q, et al.A macromolecular approach to eradicate multidrug resistant bacterial infections while mitigating drug resistance onset[J].Nature Communications, 2018, 9(1):917.
[7] ROCH M, VARELA M C, TAGLIALEGNA A, et al.Tedizolid is a promising antimicrobial option for the treatment of Staphylococcus aureus infections in cystic fibrosis patients[J].The Journal of Antimicrobial Chemotherapy, 2020, 75(1):126-134.
[8] COCHRANE S A, LI X, HE S, et al.Synthesis of tridecaptin-antibiotic conjugates with in vivo activity against Gram-negative bacteria[J].Journal of Medicinal Chemistry, 2015, 58(24):9779-9785.
[9] SCHOOLEY R T, STRATHDEE S.Treat phage like living antibiotics[J].Nature Microbiology, 2020, 5(3):391-392.
[10] HHUANG Y, WANG W, ZHANG Z, et al.Phage products for fighting antimicrobial resistance[J].Microorganisms, 2022, 10(7):1324.
[11] TKHILAISHVILIKH T, WANG L, TAVANTI A, et al.Antibacterial efficacy of two commercially available bacteriophage formulations, staphylococcal bacteriophage and PYO bacteriophage, against methicillin-resistant Staphylococcus aureus:Prevention and eradication of biofilm formation and control of a systemic infection of Galleria mellonella larvae[J].Frontiers in Microbiology, 2020, 11:110.
[12] SELLE K, FLETCHER J R, TUSON H, et al. In vivo targeting of Clostridioides difficile using phage-delivered CRISPR-Cas3 antimicrobials[J].mBio, 2020, 11(2):e00019-20.
[13] NGUYEN N T, GRELLING N, WETTELAND C L, et al.Antimicrobial activities and mechanisms of magnesium oxide nanoparticles (nMgO) against pathogenic bacteria, yeasts, and biofilms[J].Scientific Reports, 2018, 8(1):16260.
[14] HURDLE J G, O'NEILL A J, CHOPRA I, et al.Targeting bacterial membrane function:An underexploited mechanism for treating persistent infections[J].Nature Reviews Microbiology, 2011, 9(1):62-75.
[15] SHE P F, LIU Y Q, XU L L, et al.L007-0069 kills Staphylococcus aureus in high resistant phenotypes[J].Cellular and Molecular Life Sciences, 2022, 79(11):552.
[16] TALBOT G H, JEZEK A, MURRAY B E, et al.The Infectious Diseases Society of America's 10×'20 initiative (10 new systemic antibacterial agents US Food and Drug Administration approved by 2020):Is 20×'20 a possibility?[J].Clinical Infectious Diseases, 2019, 69(1):1-11.
[17] BALD D, VILLELLAS C, LU P, et al.Targeting energy metabolism in Mycobacterium tuberculosis, a new paradigm in antimycobacterial drug discovery[J].mBio, 2017, 8(2):e00272-17.
[18] BAHUGUNA A, RAWAT S, RAWAT D S.QcrB in Mycobacterium tuberculosis:The new drug target of antitubercular agents[J].Medicinal Research Reviews, 2021, 41(4):2565-2581.
[19] KRISHNAMURTHY M, LEMMON M M, FALCINELLI E M, et al.Enhancing the antibacterial activity of polymyxins using a nonantibiotic drug[J].Infection and Drug Resistance, 2019, 12:1393-1405.
[20] TZENG S R, HUANG Y W, ZHANG Y Q, et al.A celecoxib derivative eradicates antibiotic-resistant Staphylococcus aureus and biofilms by targeting YidC2 translocase[J].International Journal of Molecular Sciences, 2020, 21(23):9312.
[21] SHAHREZA M L, GHADIRI N, MOUSAVI S R, et al.A review of network-based approaches to drug repositioning[J].Briefings in Bioinformatics, 2018, 19(5):878-892.
[22] RAO N, POOJARI T, POOJARY C, et al.Drug repurposing:A shortcut to new biological entities[J].Pharmaceutical Chemistry Journal, 2022, 56(9):1203-1214.
[23] JOURDAN J P, BUREAU R, ROCHAIS C, et al.Drug repositioning:A brief overview[J].Journal of Pharmacy and Pharmacology, 2020, 72(9):1145-1151.
[24] CARLSON-BANNING K M, CHOU A, LIU Z, et al.Toward repurposing ciclopirox as an antibiotic against drug-resistant Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae[J].PLoS One, 2013, 8(7):e69646.
[25] STOKES J M, MACNAIR C R, ILYAS B, et al.Pentamidine sensitizes Gram-negative pathogens to antibiotics and overcomes acquired colistin resistance[J].Nature Microbiology, 2017, 2:17028.
[26] CEBRERO-CANGUEIRO T, ÁLVAREZl-MARÍN R, LABRADOR-HERRERA G, et al.In vitro activity of pentamidine alone and in combination with aminoglycosides, tigecycline, rifampicin, and doripenem against clinical strains of carbapenemase-producing and/or colistin-resistant Enterobacteriaceae[J].Frontiers in Cellular and Infection Microbiology, 2018, 8:363.
[27] TYERS M, WRIGHT G D.Drug combinations:A strategy to extend the life of antibiotics in the 21st century[J].Nature Reviews Microbiology, 2019, 17(3):141-155.
[28] YU Y, WALSH T R, YANG R S, et al.Novel partners with colistin to increase its in vivo therapeutic effectiveness and prevent the occurrence of colistin resistance in NDM- and MCR-co-producing Escherichia coli in a murine infection model[J].Journal of Antimicrobial Chemotherapy, 2019, 74(1):87-95.
[29] GONZÁLEZ-BELLO C.Antibiotic adjuvants-A strategy to unlock bacterial resistance to antibiotics[J].Bioorganic & Medicinal Chemistry Letters, 2017, 27(18):4221-4228.
[30] CHAWLA M, VERMA J, GUPTA R, et al.Antibiotic potentiators against multidrug-resistant bacteria:Discovery, development, and clinical relevance[J].Frontiers in Microbiology, 2022, 13:887251.
[31] SUN H, ZHANG Q, WANG R, et al.Resensitizing carbapenem- and colistin-resistant bacteria to antibiotics using auranofin[J].Nature Communications, 2020, 11(1):5263.
[32] LIU Y, JIA Y, YANG K, et al.Metformin restores tetracyclines susceptibility against multidrug resistant bacteria[J].Advanced Science, 2020, 7(12):1902227.
[33] FERNANDES P, MARTENS E.Antibiotics in late clinical development[J].Biochemical Pharmacology, 2017, 133:152-163.
[34] ZHANEL G G, LAWRENCE C K, ADAM H, et al.Imipenem-relebactam and meropenem-vaborbactam:Two novel carbapenem-β-lactamase inhibitor combinations[J].Drugs, 2018, 78(1):65-98.
[35] HINCHLIFFE P, GONZALEZ M M, MOJICA M F, et al.Cross-class metallo-beta-lactamase inhibition by bisthiazolidines reveals multiple binding modes[J].Proceedings of the National Academy of Sciences of the Nnited States of America, 2016, 113(26):E3745-E3754.
[36] WANG R, LAI T P, GAO P, et al.Bismuth antimicrobial drugs serve as broad-spectrum metallo-beta-lactamase inhibitors[J].Nature Communications, 2018, 9(1):439.
[37] WANG Y, MOWLA R, GUO L, et al.Evaluation of a series of 2-napthamide derivatives as inhibitors of the drug efflux pump AcrB for the reversal of antimicrobial resistance[J].Bioorganic & Medicinal Chemistry Letters, 2017, 27(4):733-739.
[38] SINGH S, KALIA N P, JOSHI P, et al.Boeravinone B, a novel dual inhibitor of NorA bacterial efflux pump of Staphylococcus aureus and human P-glycoprotein, reduces the biofilm formation and intracellular invasion of bacteria[J].Frontiers in Microbiology, 2017, 8:1868.
[39] SUN W, HE S, MARTÍNEZ-ROMERO C, et al.Synergistic drug combination effectively blocks Ebola virus infection[J].Antiviral Research, 2017, 137:165-172.
[40] MANOLIS E, BROGREN J, COLE S, et al.Commentary on the MID3 good practices paper[J].CPT Pharmacometrics and Systems Pharmacology, 2017, 6(7):416-417.
[41] KIMKO H, PINHEIRO J.Model-based clinical drug development in the past, present and future:A commentary[J].British Journal of Clinical Pharmacology, 2015, 79(1):108-116.
[42] PLOEGER B A, GRAAF P H, DANHOF M.Incorporating receptor theory in mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) modeling[J].Drug Metabolism and Pharmacokinetics, 2009, 24(1):3-15.
[43] KRISTOFFERSSON A N, BISSANTZ C, OKUJAVA R, et al.A novel mechanism-based pharmacokinetic-pharmacodynamic (PKPD) model describing ceftazidime/avibactam efficacy against beta-lactamase-producing Gram-negative bacteria[J].Journal of Antimicrobial Chemotherapy, 2020, 75(2):400-408.
[44] BIAN X, LIU X, CHEN Y, et al.Dose optimization of colistin combinations against carbapenem-resistant Acinetobacter baumannii from patients with hospital-acquired pneumonia in China by using an in vitro pharmacokinetic/pharmacodynamic model[J].Antimicrobial Agents and Chemotherapy, 2019, 63(4):e01989-18.
[45] SY S, ZHUANG L, XIA H, et al.Prediction of in vivo and in vitro infection model results using a semimechanistic model of avibactam and aztreonam combination against multidrug resistant organisms[J].CPT:Pharmacometrics & Systems Pharmacology, 2017, 6(3):197-207.
[46] RAMOS P I P, FERNÁNDEZ D P, LANZAROTTI E, et al.An integrative, multi-omics approach towards the prioritization of Klebsiella pneumoniae drug targets[J].Scientific Reports, 2018, 8(1):10755.
[47] HENDRIKSEN R S, BORTOLAIA V, TATE H, et al.Using genomics to track global antimicrobial resistance[J].Frontiers in Public Health, 2019, 7:242.
[48] PORNSUKAROM S, VLIET A H M, THAKUR S.Whole genome sequencing analysis of multiple Salmonella serovars provides insights into phylogenetic relatedness, antimicrobial resistance, and virulence markers across humans, food animals and agriculture environmental sources[J].BMC Genomics, 2018, 19(1):801.
[49] RICHARDS V P, VELSKO I M, ALAM T, et al.Population gene introgression and high genome plasticity for the zoonotic pathogen Streptococcus agalactiae[J].Molecular Biology and Evolution, 2019, 36(11):2572-2590.
[50] BRUGER E L, MARX C J.A decade of genome sequencing has revolutionized studies of experimental evolution[J].Current Opinion in Microbiology, 2018, 45:149-155.
[51] DEATHERAGE D E, BARRICK J E.Identification of mutations in laboratory-evolved microbes from next-generation sequencing data using breseq[J].Methods in Molecular Biology, 2014, 1151:165-188.
[52] KHOURY J Y, MAURE A, GINGRAS H, et al.Chemogenomic screen for imipenem resistance in Gram-negative bacteria[J].mSystems, 2019, 4(6):e00465-19.
[53] DING T, LI T, LI J.Identification of natural product compounds as quorum sensing inhibitors in Pseudomonas fluorescens P07 through virtual screening[J].Bioorganic & Medicinal Chemistry, 2018, 26(14):4088-4099.
[54] BALTZ R H.Natural product drug discovery in the genomic era:Realities, conjectures, misconceptions, and opportunities[J].Journal of Industrial Microbiology & Biotechnology, 2019, 46(3-4):281-299.
[55] MOK S, ASHLEY E A, FERREIRA P E, et al.Drug resistance.Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance[J].Science, 2015, 347(6220):431-435.
[56] SINGHANIA A, WILKINSON R J, RODRIGUE M, et al.The value of transcriptomics in advancing knowledge of the immune response and diagnosis in tuberculosis[J].Nature Immunology, 2018, 19(11):1159-1168.
[57] CANELLAS A L B, DA COSTA W F, FREITAS S J, et al.In sickness and in health:Insights into the application of omics in aquaculture settings under a microbiological perspective[J].Aquaculture, 2022, Online ahead of print.
[58] MAHDAVI MASHAKI K, GARG V, NASROLLAHNEZHAD GHOMI A A, et al.RNA-Seq analysis revealed genes associated with drought stress response in kabuli chickpea (Cicer arietinum L.)[J].PLoS One, 2018, 13(6):e0199774.
[59] ZHU J H, WANG B W, PAN M, et al.Rifampicin can induce antibiotic tolerance in mycobacteria via paradoxical changes in rpoB transcription[J].Nature Communications, 2018, 9(1):4218.
[60] CHOE D, SZUBIN R, DAHESH S, et al.Genome-scale analysis of methicillin-resistant Staphylococcus aureus USA300 reveals a tradeoff between pathogenesis and drug resistance[J].Scientific Reports, 2018, 8(1):2215.
[61] ZHAO J, CHEAH S E, ROBERTS K D, et al.Transcriptomic analysis of the activity of a novel polymyxin against Staphylococcus aureus[J].mSphere, 2016, 1(4):e00119-16.
[62] QIN H, LO N W, LOO J F, et al.Comparative transcriptomics of multidrug-resistant Acinetobacter baumannii in response to antibiotic treatments[J].Scientific Reports, 2018, 8(1):3515.
[63] HAN M L, LIU X, VELKOV T, et al.Metabolic analyses revealed time-dependent synergistic killing by colistin and aztreonam combination against multidrug-resistant Acinetobacter baumannii[J].Frontiers in Microbiology, 2018, 9:2776.
[64] HOERR V, DUGGAN G E, ZBYTNUIK L, et al.Characterization and prediction of the mechanism of action of antibiotics through NMR metabolomics[J].BMC Microbiology, 2016, 16:82.
[65] ZHAO J, HAN M L, ZHU Y, et al.Comparative metabolomics reveals key pathways associated with the synergistic activity of polymyxin B and rifampicin combination against multidrug-resistant Acinetobacter baumannii[J].Biochemical Pharmacology, 2021, 184:114400.
[66] SCHELLI K, ZHONG F, ZHU J.Comparative metabolomics revealing Staphylococcus aureus metabolic response to different antibiotics[J].Microbial Biotechnology, 2017, 10(6):1764-1774.
[67] CAMPOS A I, ZAMPIERI M.Metabolomics-driven exploration of the chemical drug space to predict combination antimicrobial therapies[J].Molecular Cell, 2019, 74(6):1291-1303.e6.
[68] ABREU A C, COQUEIRO A, SULTAN A R, et al.Looking to nature for a new concept in antimicrobial treatments:Isoflavonoids from Cytisus striatus as antibiotic adjuvants against MRSA[J].Scientific Reports, 2017, 7(1):3777.
[69] MAIFIAH M H, CREEK D J, NATION R L, et al.Untargeted metabolomics analysis reveals key pathways responsible for the synergistic killing of colistin and doripenem combination against Acinetobacter baumannii[J].Scientific Reports, 2017, 7:45527.
[70] LIAW C C, CHEN PC, SHIH C J, et al.Vitroprocines, new antibiotics against Acinetobacter baumannii, discovered from marine Vibrio sp.QWI-06 using mass-spectrometry-based metabolomics approach[J].Scientific Reports, 2015, 5:12856.