RRC ID 53698
著者 Amato SM, Brynildsen MP.
タイトル Persister Heterogeneity Arising from a Single Metabolic Stress.
ジャーナル Curr Biol
Abstract Persisters are phenotypic variants present within isogenic bacterial populations that exhibit extreme tolerance toward antibiotic stress. We previously elucidated a mechanistic pathway by which Escherichia coli persisters to ofloxacin form in response to a carbon source transition. Here, we examine how persisters to ampicillin form from the same metabolic stress and identify the shared and unique elements of the persister formation pathways. We discovered that diauxie-dependent formation of ampicillin persisters required RelA and that loss of clpA, ssrA, or smpB eliminated persister formation through relaxation of the stringent response. Further, we found that tolerance to ampicillin was achieved through broad inhibition of peptidoglycan biosynthesis, as evidenced by the formation of persisters to antibiotics that target enzymes in different areas of that biosynthetic pathway. Interestingly, ppGpp was required for formation of both ampicillin and ofloxacin persisters, and we demonstrated that higher synthesis of the alarmone was needed to increase persisters to ampicillin compared to ofloxacin. Further, we found trans-translation and DksA to be common mediators of both pathways, whereas ClpA was unique for ampicillin persisters and nucleoid-associated proteins were unique for ofloxacin persisters. These results highlight the need to consider an antibiotic's mode of action when analyzing persister formation, demonstrate that individual stresses can produce persister heterogeneity, and emphasize the importance of identifying each respective pathway to identify common mediators that possess the most therapeutic potential to combat persisters.
巻・号 25(16)
ページ 2090-8
公開日 2015-8-17
DOI 10.1016/j.cub.2015.06.034
PII S0960-9822(15)00728-9
PMID 26255847
MeSH Adaptation, Physiological / drug effects Ampicillin / pharmacology* Anti-Bacterial Agents / pharmacology* Escherichia coli / genetics Escherichia coli / physiology* Escherichia coli Proteins / genetics Escherichia coli Proteins / metabolism Microbial Viability / drug effects* Microbial Viability / genetics Protein Biosynthesis / drug effects Signal Transduction / drug effects* Stress, Physiological
IF 9.601
引用数 57
リソース情報
原核生物(大腸菌)