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H2S Sensing via Reactive Sulfur Species (RSS) in the Human Pathogens Enterococcus faecalis and Acinetobacter baumannii
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H2S Sensing via Reactive Sulfur Species (RSS) in the Human Pathogens Enterococcus faecalis and Acinetobacter baumannii
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H2S Sensing via Reactive Sulfur Species (RSS) in the Human Pathogens Enterococcus faecalis and Acinetobacter baumannii
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Dissertation
H2S Sensing via Reactive Sulfur Species (RSS) in the Human Pathogens Enterococcus faecalis and Acinetobacter baumannii
2021
Overview
Hydrogen sulfide (H2S) is implicated as a cytoprotective agent that bacteria utilize in response to host-induced stressors such as oxidative stress and antibiotics. The physiological benefits often attributed to H2S however, are likely a result of downstream, more oxidized forms of sulfur collectively termed reactive sulfur species (RSS). RSS include the organic persulfide (RSSH), which is thought to react with reactive oxygen species at sites of infection while also inactivating -lactam antibiotics. While our understanding of H2S/RSS at the host-pathogen interface continues to improve, comparatively little is known about the mechanisms by which bacteria maintain sulfide/RSS homeostasis and what cellular processes are negatively impacted by H2S/RSS toxicity. Here, we investigate sulfide homeostasis in two major human pathogens associated with nosocomial infections, the commensal Enterococcus faecalis (E. faecalis) and Acinetobacter baumannii (A. baumannii), as well as their physiological response to exogenous sulfide. We find that E. faecalis and A. baumannii encode for remarkably distinct RSS-sensing transcriptional regulators that regulate genes that encode enzymes that are known or projected to be involved in the biogenesis of RSS from H2S and subsequent clearance of RSS from cells. These bacteria harbor significant levels of RSS as low molecular weight (LMW) persulfides, including coenzyme A persulfide (CoASSH), which are perturbed by exogenously added disodium sulfide. We find that proteome S-sulfuration (persulfidation), a posttranslational modification (PTM) implicated in H2S signaling, is widespread in these organisms. In E. faecalis, proteome persulfidation is significantly increased by exogenous sulfide in enzymes associated with fatty acid and acetyl-CoA biosynthesis. In addition, we find that exogenous sulfide significantly impacts the speciation of fatty acids as well as cellular concentrations of acetyl-CoA suggesting protein persulfidation may impact flux through these pathways. Lastly, we show that CoASSH is a potent inhibitor of E. faecalis phosphotransacetylase suggesting that a major metabolic consequence of increased levels of H2S/RSS is over-persulfidation of this key metabolite. In summary, this work expands our understanding of the molecular mechanisms that maintain H2S/RSS homeostasis and the physiological impact of exogenous sulfide in two major human pathogens, while highlighting the therapeutic potential of targeting sulfide homeostasis systems in bacterial infections.
