Metabolites augment oxidative stress to sensitize antibiotic-tolerant Staphylococcus aureus to fluoroquinolones

mBio, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 30, 2024

ABSTRACT If left unchecked, infections involving antibiotic-refractory bacteria are expected to cause millions of deaths per year in the coming decades. Beyond genetically resistant bacteria, persisters, which susceptible cells that survive antibiotic doses kill rest clonal population, can potentially contribute treatment failure and infection relapse. Stationary-phase bacterial cultures enriched with it has been shown stimulating these populations exogenous nutrients reduce persistence different classes antibiotics, including topoisomerase-targeting fluoroquinolones (FQs). In this study, we show adding glucose amino acids nutrient-starved Staphylococcus aureus enhanced their sensitivity FQs, delafloxacin (Dela)—a drug was recently approved for treating staphylococcal infections. We found while added increased nucleic acid synthesis, increase not required sensitize S. FQs. further demonstrate addition increases membrane potential ability generate harmful reactive oxygen species (ROS) during FQ treatment. Chelating iron, scavenging hydroxyl radicals, limiting oxygenation recovery following rescued nutrient-stimulated . all, our data suggest nutrient stimulation activity targets stationary-phase , resulting generation ROS, presumably made possible through metabolic upregulation, is primary driver drugs. IMPORTANCE causes many chronic relapsing because its endure host immunity therapy. While several studies have focused on requirements formation maintenance infections, effects environment responses remain understudied. Here, starved activates biosynthetic processes, DNA but oxidants sensitizes Our results development approaches aimed at perturbing metabolism increasing oxidative stress potentiate bactericidal FQs against antibiotic-tolerant

Language: Английский

Constitutive Activation of RpoH and the Addition of L-arabinose Influence Antibiotic Sensitivity of PHL628 E. coli

Antibiotics, Journal Year: 2024, Volume and Issue: 13(2), P. 143 - 143

Published: Feb. 1, 2024

Antibiotics are used to combat the ever-present threat of infectious diseases, but bacteria continually evolving an assortment defenses that enable their survival against even most potent treatments. While demand for novel antibiotic agents is high, discovery a new agent exceedingly rare. We chose focus on understanding how different signal transduction pathways in gram-negative bacterium Escherichia coli (E. coli) influence sensitivity organism antibiotics from three classes: tetracycline, chloramphenicol, and levofloxacin. Using PHL628 strain E. coli, we exogenously overexpressed two transcription factors, FliA RpoH.I54N (a constitutively active mutant), determine minimum inhibitory concentration (MIC) duration killing (MDK) each studied antibiotics. hypothesized activating these pathways, which upregulate genes respond specific stressors, could mitigate bacterial response treatment. also compared exogenous overexpression RpoH mutant thermal heat shock has feedback loops maintained. had no impact MIC or tolerance, reduced tetracycline chloramphenicol independent tolerance. Thermal alone did not affect L-arabinose, small molecule induce expression our system, unexpectedly independently increased MICs (>2-fold) levofloxacin (3-fold). Additionally, combination arabinose provided synergistic, 5-fold increase chloramphenicol. Arabinose as assessed by MDK99, (2-fold) (4-fold). These experiments highlight potential pathway modulate emerging implication enhanced

Language: Английский