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Bacterial persisters: molecular mechanisms and therapeutic development

SIGNAL TRANSDUCTION AND TARGETED THERAPY 2024年第1期9卷 1-32页

作者： Niu, Hongxia Gu, Jiaying Zhang, Ying Zhejiang Chinese Med Univ Sch Basic Med Sci Hangzhou 310053 Zhejiang Peoples R China Zhejiang Chinese Med Univ Key Lab Blood Stasis Toxin Syndrome Zhejiang Prov Hangzhou 310053 Zhejiang Peoples R China Zhejiang Univ Affiliated Hosp 1 Sch Med State Key Lab Diag & Treatment Infect Dis Hangzhou 310003 Zhejiang Peoples R China Jinan Microecol Biomed Shandong Lab Jinan 250022 Shandong Peoples R China

Persisters refer to genetically drug susceptible quiescent (non-growing or slow growing) bacteria that survive in stress environments such as antibiotic exposure, acidic and starvation conditions. These cells can regrow after stress removal and remain susceptible to the same stress. Persisters are underlying the problems of treating chronic and persistent infections and relapse infections after treatment, drug resistance development, and biofilm infections, and pose significant challenges for effective treatments. Understanding the characteristics and the exact mechanisms of persister formation, especially the key molecules that affect the formation and survival of the persisters is critical to more effective treatment of chronic and persistent infections. Currently, genes related to persister formation and survival are being discovered and confirmed, but the mechanisms by which bacteria form persisters are very complex, and there are still many unanswered questions. This article comprehensively summarizes the historical background of bacterial persisters, details their complex characteristics and their relationship with antibiotic tolerant and resistant bacteria, systematically elucidates the interplay between various bacterial biological processes and the formation of persister cells, as well as consolidates the diverse anti-persister compounds and treatments. We hope to provide theoretical background for in-depth research on mechanisms of persisters and suggest new ideas for choosing strategies for more effective treatment of persistent infections.

关键词： SMALL-COLONY VARIANTS TOXIN-ANTITOXIN SYSTEMS UROPATHOGENIC ESCHERICHIA-COLI NONCULTURABLE VIBRIO-CHOLERAE MEDIATE ANTIBIOTIC tolerance STAPHYLOCOCCUS-AUREUS MYCOBACTERIUM-TUBERCULOSIS PSEUDOMONAS-AERUGINOSA STATIONARY-PHASE multidrug tolerance

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Quaternary ammonium-induced multidrug tolerant Streptococcus mutans persisters elevate cariogenic virulence in vitro

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International Journal of Oral Science 2017年第4期9卷 224-231页

作者： Ya-Ling Jiang Wei Qiu Xue-Dong Zhou Hao Li Jun-Zhuo Lu Hockin HK Xu Xian Peng Ming-Yun Li Ming-Ye Feng Lei Cheng Biao Ren State Key Laboratory of Oral Diseases&National Clinical Research Center for Oral Diseases&Department of Operative Dentistry and Endodontics West China Hospital of StomatologySichuan UniversityChengduChina Biomaterials&Tissue Engineering Division Department of EndodonticsProsthodontics and Operative DentistryUniversity of Maryland Dental SchoolBaltimoreUSA

Dental caries are the most prevalent chronic infections in the oral cavity, and Streptococcus mutans acts as the main cariogenic bacterial species. Antibacterial quaternary ammonium compounds （QAs） have been developed to preveFnt or treat dental caries. However, there is no report on the tolerance of S. mutans to QAs. In this study, we investigated the development of S. mutans persistence induced by a novel dental caries defensive agent, dimethylaminododecyl methacrylate （DMADDM）, for the first time. Typical biphasic killing kinetics for persisters were observed in both S. mutans planktonic and biofilm cultures challenged by DMADDM at concentrations of 20 and 200 ***- z respectively. The persisters tolerated six other antibiotics with different antibacterial mechanisms, while only daptomycin and vancomycin could slightly reduce the persister numbers in planktonic cultures. The distribution of persisters in DMADDM-treated biofilms was similar to that in the untreated control, except that the total biomass and biofilm height were significantly reduced. A higher exopolysaccharides （EPS）：bacteria ratio was observed in DMADDM-treated biofilms. Persisters in biofilms significantly upregulated gtf gene expression, indicating an increase in the bacteria＇s ability to produce EPS and an elevated capability of cariogenic virulence. Carbon source metabolism was significantly reduced, as related metabolic genes were all downregulated in persisters. Concentrations of 0.1 mM, 1 mM and 10 mM of extra glucose significantly reduced the number of persisters both in planktonic and biofilm conditions. The formation of non- inheritable and multidrug tolerant persisters induced by DMADDM suggested that drug tolerance and new persistent eradication strategies should be considered for oral antibacterial agents.

关键词： antibacterial quaternary ammoniums dental caries persistence multidrug tolerance Streptococcus mutans biofilms

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