A broadly applicable, stress-mediated bacterial death pathway regulated by the phosphotransferase system (PTS) and the cAMP-Crp cascade

Abstract

Significance Finding that pan-tolerance derives from defects in carbohydrate regulation connects stress-mediated lesions with metabolic change, identifies a stable type of tolerance, and demonstrates a widely shared death response. Manipulation of the response should improve antimicrobial efficacy, preserve beneficial bacteria during antimicrobial use, and protect industrial bacteria from toxic products. Mutations in many genes can interfere with stress-mediated metabolism; thus, mutation to pan-tolerance could be a high-probability event. Finding that selection of tolerance to one lethal stressor confers tolerance to many, if not all, indicates that massive disinfectant consumption potentially undermines antimicrobial efficacy and immune defenses against pathogenic bacteria. Since pan-tolerance is hidden from current surveillance of resistance, the work indicates a need for facile methods to measure tolerance.

The very hungry bactericidal antibiotics

“…The current study from Zeng et al. ( 8 ) continues the riveting exploration of the metabolic dependence of many bactericidal antibiotics. The authors establish that the PTS system, via metabolic remodeling, contributes to the lethality of bactericidal antibiotics.…”

“…In PNAS, Zeng et al. ( 8 ) bring to the limelight the role of a key metabolic regulatory system in the susceptibility of bacteria to the lethality of bactericidal antibiotics. Previous studies mapped high-tolerance mutants from experiments wherein cycles of antibiotic treatment, antibiotic removal, and recovery of cells enrich for tolerant mutants ( 9 ).…”

“…Zeng et al. ( 8 ) were able to reproduce the phenotype of the pan-tolerant mutant with a gene knockout of ptsI , suggesting that the isolated mutant from the enrichment experiments had a loss-of-function mutation in ptsI . Next, the authors explored the effect of chemical inhibition of EI.…”

“…Perhaps. The authors rule out a contribution from some PTS transporters to the pan-tolerant phenotype ( 8 ). Antibiotic tolerance of the mutants with the knockouts of EIIB genes ( ptsG , malX , ascF , and glvC ) is indistinguishable from that of parental WT.…”

Fluoroquinolone heteroresistance, antimicrobial tolerance, and lethality enhancement

“…T h e s e s t u d i e s o f fluoroquinolones are likely to be of broad interest, because some of the principles appear to apply to antimicrobials in general. For example, heteroresistance is a general property of bacteria, and the death pathway appears to be common to antibiotics, disinfectants, and environmental stress (Zeng et al, 2022). We begin by discussing two key characteristics of bacteria, resistance and tolerance.…”