Staphylococcus aureus lactate‐ and malate‐quinone oxidoreductases contribute to nitric oxide resistance and virulence

Abstract

Summary Staphylococcus aureus is a Gram-positive pathogen that resists many facets of innate immunity including nitric oxide (NO·). S. aureus NO·-resistance stems from its ability to evoke a metabolic state that circumvents the negative effects of reactive nitrogen species. The combination of L-lactate and peptides promotes S. aureus growth at moderate NO·-levels, however neither nutrient alone suffices. Here we investigate the staphylococcal malate-quinone and L-lactate-quinone oxidoreductases (Mqo and Lqo), both of which are critical during NO·-stress for the combined utilization of peptides and L-lactate. We address the specific contributions of Lqo-mediated L-lactate utilization and Mqo-dependent amino acid consumption during NO·-stress. We show that Lqo conversion of L-lactate to pyruvate is required for the formation of ATP, an essential energy source for peptide utilization. Thus, both Lqo and Mqo are essential for growth under these conditions making them attractive candidates for targeted therapeutics. Accordingly, we exploited a modeled Mqo/Lqo structure to define the catalytic and substrate-binding residues. We also compare the S. aureus Mqo/Lqo enzymes to their close relatives throughout the staphylococci and explore the substrate specificities of each enzyme. This study provides the initial characterization of the mechanism of action and the immunometabolic roles for a newly defined staphylococcal enzyme family.

Amino Acid Catabolism in Staphylococcus aureus and the Function of Carbon Catabolite Repression

“…As the abscess matures within the fibrin wall, the center includes a large cluster of viable cells called the staphylococcal abscess community ( 12 , 14 ). It is hypothesized that these niches have low concentrations of NO, allowing respiratory activity ( 5 , 15 ); however, it is predicted that S. aureus must grow on nonpreferred carbon sources, as glucose is not abundant ( 6 , 16 ). Indeed, S. aureus lacks the ability to utilize phospholipids, triglycerides, and potentially other short-chain fatty acids as carbon sources due to the lack of both β-oxidation and glyoxylate shunt pathways.…”

Identification of the main glutamine and glutamate transporters in Staphylococcus aureus and their impact on c‐di‐AMP production

“…Sensitive regulatory mechanisms enable this organism to rapidly respond to external stimuli and environmental changes. Amongst others, this allows bacteria to adapt their metabolism and utilize different carbon and nitrogen sources available in each specific niche (Crooke et al, ; Fridkin et al, ; Fuller et al, ; Halsey et al, ; Lehman et al, ; Richardson, Libby, & Fang, ; Spahich, Vitko, Thurlow, Temple, & Richardson, ; Vitko, Spahich, & Richardson, ).…”

SbnI is a free serine kinase that generates -phospho-l-serine for staphyloferrin B biosynthesis in

“…abscesses, glucose is limiting, and S. aureus probably survives through catabolism of secondary carbon sources, specifically lactate, peptides, and free amino acids (46,52,53). Resultant changes in the central metabolism of S. aureus may not severely hinder SB biosynthesis due to the modularity of the sbn system.…”