A multifaceted cellular damage repair and prevention pathway promotes high-level tolerance to β-lactam antibiotics.

TitleA multifaceted cellular damage repair and prevention pathway promotes high-level tolerance to β-lactam antibiotics.
Publication TypeJournal Article
Year of Publication2021
AuthorsShin J-H, Choe D, Ransegnola B, Hong H-R, Onyekwere I, Cross T, Shi Q, Cho B-K, Westblade LF, Brito IL, Dörr T
JournalEMBO Rep
Date Published2021 02 03
KeywordsAnimals, Anti-Bacterial Agents, beta-Lactams, Cell Wall, Mice, Vibrio cholerae

Bactericidal antibiotics are powerful agents due to their ability to convert essential bacterial functions into lethal processes. However, many important bacterial pathogens are remarkably tolerant against bactericidal antibiotics due to inducible damage repair responses. The cell wall damage response two-component system VxrAB of the gastrointestinal pathogen Vibrio cholerae promotes high-level β-lactam tolerance and controls a gene network encoding highly diverse functions, including negative control over multiple iron uptake systems. How this system contributes to tolerance is poorly understood. Here, we show that β-lactam antibiotics cause an increase in intracellular free iron levels and collateral oxidative damage, which is exacerbated in the ∆vxrAB mutant. Mutating major iron uptake systems dramatically increases ∆vxrAB tolerance to β-lactams. We propose that VxrAB reduces antibiotic-induced toxic iron and concomitant metabolic perturbations by downregulating iron uptake transporters and show that iron sequestration enhances tolerance against β-lactam therapy in a mouse model of cholera infection. Our results suggest that a microorganism's ability to counteract diverse antibiotic-induced stresses promotes high-level antibiotic tolerance and highlights the complex secondary responses elicited by antibiotics.

Alternate JournalEMBO Rep
PubMed ID33463026
PubMed Central IDPMC7857431
Grant ListR01 AI143704 / AI / NIAID NIH HHS / United States
1DP2HL141007 / NH / NIH HHS / United States
R01 GM130971 / GM / NIGMS NIH HHS / United States
DP2 HL141007 / HL / NHLBI NIH HHS / United States
R01AI143704 / NH / NIH HHS / United States
R01GM130971 / NH / NIH HHS / United States
Related Faculty: 
Lars Westblade, Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
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