title: TCA cycle-mediated generation of ROS is a key mediator for HeR-MRSA survival under β-lactam antibiotic exposure.
abstract: Methicillin-resistant Staphylococcus aureus (MRSA) is a major multidrug resistant pathogen responsible for several difficult-to-treat infections in humans. Clinical Hetero-resistant (HeR) MRSA strains, mostly associated with persistent infections, are composed of mixed cell populations that contain organisms with low levels of resistance (hetero-resistant HeR) and those that display high levels of drug resistance (homo-resistant HoR). However, the full understanding of β-lactam-mediated HeR/HoR selection remains to be completed. In previous studies we demonstrated that acquisition of the HoR phenotype during exposure to β-lactam antibiotics depended on two key elements: (1) activation of the SOS response, a conserved regulatory network in bacteria that is induced in response to DNA damage, resulting in increased mutation rates, and (2) adaptive metabolic changes redirecting HeR-MRSA metabolism to the tricarboxylic acid (TCA) cycle in order to increase the energy supply for cell-wall synthesis. In the present work, we identified that both main mechanistic components are associated through TCA cycle-mediated reactive oxygen species (ROS) production, which temporally affects DNA integrity and triggers activation of the SOS response resulting in enhanced mutagenesis. The present work brings new insights into a role of ROS generation on the development of resistance to β-lactam antibiotics in a model of natural occurrence, emphasizing the cytoprotective role in HeR-MRSA survival mechanism.
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Houston, Texas, United States of America.
authors.forename: Roberto R
authors.initials: RR
authors.lastname: Rosato
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Houston, Texas, United States of America.
authors.forename: Regina
authors.initials: R
authors.lastname: Fernandez
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Houston, Texas, United States of America.
authors.forename: Liliana I
authors.initials: LI
authors.lastname: Paz
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Houston, Texas, United States of America.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Singh
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Houston, Texas, United States of America; Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas, United States of America.
authors.forename: Adriana E
authors.initials: AE
authors.lastname: Rosato
mesh_terms: D015082:2,2'-Dipyridyl / Q000494:pharmacology; D000222:Adaptation, Physiological; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000502:physiology; D002952:Citric Acid Cycle / Q000502:physiology*; D004249:DNA Damage; D004269:DNA, Bacterial / Q000032:analysis; D024901:Drug Resistance, Multiple, Bacterial / Q000502:physiology*; D020869:Gene Expression Profiling; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D059645:Mutation Rate; D010068:Oxacillin / Q000494:pharmacology; D046915:Penicillin-Binding Proteins / Q000235:genetics / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D013014:SOS Response, Genetics; D013890:Thiourea / Q000494:pharmacology; D018440:beta-Lactam Resistance / Q000502:physiology*; D047090:beta-Lactams / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004269:DNA, Bacterial; D046915:Penicillin-Binding Proteins; D017382:Reactive Oxygen Species; D047090:beta-Lactams; C487789:mecA protein, Staphylococcus aureus; D015082:2,2'-Dipyridyl; D013890:Thiourea; D010068:Oxacillin