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PLoS One. 2014 Jun 16;9(6):e99605. doi: 10.1371/journal.pone.0099605. eCollection 2014.

TCA cycle-mediated generation of ROS is a key mediator for HeR-MRSA survival under β-lactam antibiotic exposure.

Author information

1
Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Houston, Texas, United States of America.
2
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.

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.

PMID:
24932751
PMCID:
PMC4059655
DOI:
10.1371/journal.pone.0099605
[Indexed for MEDLINE]
Free PMC Article

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