Abstract
Antibiotic persistence describes the presence of phenotypic variants within an isogenic bacterial population that are transiently tolerant to antibiotic treatment. Perturbations of metabolic homeostasis can promote antibiotic persistence, but the precise mechanisms are not well understood. Here, we use laboratory evolution, population-wide sequencing and biochemical characterizations to identify mutations in respiratory complex I and discover how they promote persistence in Escherichia coli. We show that persistence-inducing perturbations of metabolic homeostasis are associated with cytoplasmic acidification. Such cytoplasmic acidification is further strengthened by compromised proton pumping in the complex I mutants. While RpoS regulon activation induces persistence in the wild type, the aggravated cytoplasmic acidification in the complex I mutants leads to increased persistence via global shutdown of protein synthesis. Thus, we propose that cytoplasmic acidification, amplified by a compromised complex I, can act as a signaling hub for perturbed metabolic homeostasis in antibiotic persisters.
Highlights
Antibiotic persistence describes the presence of phenotypic variants within an isogenic bacterial population that are transiently tolerant to antibiotic treatment
To discover genetic determinants of persister cell formation upon perturbations of metabolic homeostasis, we exploited laboratory evolution selecting for increased persistence in an environment that cycles between dilution and regrowth to stationary phase and antibiotic treatments (Fig. 1a)[8,10,48]
As overall 38.3% of each evolved population consists of nuo alleles (Supplementary Fig. 1m), we find that the nuo operon is the major target of evolution towards high persistence in our laboratory evolution experiment selecting for increased antibiotic survival upon perturbation of metabolic homeostasis through entry into stationary phase
Summary
Antibiotic persistence describes the presence of phenotypic variants within an isogenic bacterial population that are transiently tolerant to antibiotic treatment. We propose that cytoplasmic acidification, amplified by a compromised complex I, can act as a signaling hub for perturbed metabolic homeostasis in antibiotic persisters. Metabolic perturbations like diauxic[28] and rapid nutrient shifts[26,38] and entry in stationary phase[3,39,40] induce persister cell formation, where certain rapid carbon shifts can force almost an entire population into an antibiotic-tolerant state in a metabolic fluxdependent manner[38]. Complex I mutants with increased persistence display compromised proton translocation leading to significant cytoplasmic acidification upon perturbations of metabolic homeostasis. Our findings show how cytoplasmic acidification, amplified by a compromised complex I, acts as a central signaling hub to connect a perturbed metabolic homeostasis with persister cell formation
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