Abstract
Staphylococcus aureus 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 msaABCR in several important staphylococcal phenotypes, including the formation of persister cells. Additionally, observations of the regulation of several metabolic genes by the msaABCR operon in transcriptomics and proteomics analyses have suggested its role in the metabolic activities of S. aureus. Given the importance of metabolism in persister formation as our starting point, in this study we demonstrated how the msaABCR operon regulates energy metabolism and subsequent antibiotic tolerance. We showed that deletion of the msaABCR operon results in increased tricarboxylic acid (TCA) cycle activity, accompanied by increased cellular ATP content and higher NADH content in S. aureus cells. We also showed that msaABCR (through MsaB) represses the ccpE and ndh2 genes, thereby regulating TCA cycle activity and the generation of membrane potential, respectively. Together, the observations from this study led to the conclusion that msaABCR operon deletion induces a metabolically hyperactive state, leading to decreased persister formation in S. aureus.
Highlights
Staphylococcus aureus is a prominent human pathogen that causes systemic diseases, including infective endocarditis, osteomyelitis, bacteremia, and pneumonia (Lowy, 1998)
Based upon previous work from our laboratory (Sahukhal et al, 2017), we hypothesized that the deletion of the msaABCR operon in S. aureus cells would result in increased metabolic activity, inducing a higher energy state that prevents persister cell formation
We examined tricarboxylic acid (TCA) cycle activity by measuring the expression of TCA genes in late exponential growth phase via quantitative realtime PCR
Summary
Staphylococcus aureus is a prominent human pathogen that causes systemic diseases, including infective endocarditis, osteomyelitis, bacteremia, and pneumonia (Lowy, 1998). These infections are typically caused by device-associated biofilms that harbor persister cells (Lafleur et al, 2010; Lewis, 2010; Conlon et al, 2015). The clinical relevance of S. aureus persister cells is increasingly understood, as evidenced by their reported presence in recurring infections (Becker et al, 2014; Conlon, 2014). Studies have so far demonstrated an association between the depletion of intracellular ATP and the formation of persister cells in major bacterial pathogens, including S. aureus, Escherichia coli, and Pseudomonas aeruginosa (Conlon et al, 2016; Shan et al, 2017; Cameron et al, 2018)
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