AUTHOR=Pandey Shanti , Sahukhal Gyan S. , Elasri Mohamed O. 

TITLE=The msaABCR Operon Regulates Persister Formation by Modulating Energy Metabolism in Staphylococcus aureus

JOURNAL=Frontiers in Microbiology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2021.657753

DOI=10.3389/fmicb.2021.657753

ISSN=1664-302X

ABSTRACT=<p><italic>Staphylococcus aureus</italic> is a major human pathogen that causes chronic, systemic infections, and the recalcitrance of these infections is mainly due to the presence of persister cells, which are a bacterial subpopulation that exhibits extreme, yet transient, antibiotic tolerance accompanied by a transient halt in growth. However, upon cessation of antibiotic treatment, a resumption in growth of persister cells causes recurrence of infections and treatment failure. Previously, we reported the involvement of <italic>msaABCR</italic> in several important staphylococcal phenotypes, including the formation of persister cells. Additionally, observations of the regulation of several metabolic genes by the <italic>msaABCR</italic> operon in transcriptomics and proteomics analyses have suggested its role in the metabolic activities of <italic>S. aureus</italic>. Given the importance of metabolism in persister formation as our starting point, in this study we demonstrated how the <italic>msaABCR</italic> operon regulates energy metabolism and subsequent antibiotic tolerance. We showed that deletion of the <italic>msaABCR</italic> operon results in increased tricarboxylic acid (TCA) cycle activity, accompanied by increased cellular ATP content and higher NADH content in <italic>S. aureus</italic> cells. We also showed that <italic>msaABCR</italic> (through MsaB) represses the <italic>ccpE</italic> and <italic>ndh</italic><sub>2</sub> genes, thereby regulating TCA cycle activity and the generation of membrane potential, respectively. Together, the observations from this study led to the conclusion that <italic>msaABCR</italic> operon deletion induces a metabolically hyperactive state, leading to decreased persister formation in <italic>S. aureus</italic>.</p>