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A multifaceted cellular damage repair and prevention pathway promotes high‐level tolerance to β‐lactam antibiotics
Author(s) -
Shin JungHo,
Choe Donghui,
Ransegnola Brett,
Hong HyeRim,
Onyekwere Ikenna,
Cross Trevor,
Shi Qiaojuan,
Cho ByungKwan,
Westblade Lars F,
Brito Ilana L,
Dörr Tobias
Publication year - 2021
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.202051790
Subject(s) - multidrug tolerance , antibiotics , biology , microbiology and biotechnology , efflux , vibrio cholerae , pathogen , bacteria , genetics , biofilm
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.

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