Fatty acids can inhibit Staphylococcus aureus SaeS activity at the membrane independent of alterations in respiration

Abstract

According to the Centers of Disease Control and Prevention (CDC), approximately 2.8 million people in the U.S. are infected by antibiotic-resistant bacteria each year. It is estimated that antibioticresistant Staphylococcus aureus accounted for over 300,000 hospitalizations and over 10,000 deaths in 2017, indicating that S. aureus is a key contributor to the burden of antibiotic-resistant infections (CDC). S. aureus is a Gram-positive bacterium that asymptomatically colonizes 20%-30% of the population, predominately in the anterior nares and the skin (Lowy, 1998). Despite being asymptomatic, S. aureus can opportunistically establish infections in nearly every anatomical site but most commonly causes infections in the skin (Pallin et al., 2008;Suaya et al., 2014). This bacterium is responsible for most of the skin and soft-tissue infections observed in the clinic (Moran et al., 2006) and was estimated to cost the U.S. healthcare system $1.7 billion in 2017 (CDC). With the large burden that S. aureus places on the healthcare system, an emphasis on understanding what makes S. aureus such a successful pathogen and designing novel targeted therapeutics is needed. S. aureus must be able to adapt to individual niches on and withinthe host to ensure well-timed regulation of its virulence arsenal to be a successful pathogen. Environmental cues include changes in osmolarity, temperature, presence, or absence of oxygen, pH, and host-associated factors. Some of these signals are sensed by two-component systems (TCS) which allow bacteria to respond to stimuli and adjust target gene expression accordingly (Tiwari et al., 2017;Wang, 2012). S. aureus possesses 16 TCS that respond to

Regulation of the Sae Two-Component System by Branched-Chain Fatty Acids in Staphylococcus aureus

“…Recent publications have uncovered new links between membrane composition and SaeS activation in S. aureus ( 49 , 54 ). Previous work demonstrated that SaeS is inhibited by both saturated and unsaturated straight-chain fatty acids; in contrast, this study reveals BCFAs are activators of SaeS kinase activity in vivo .…”

Prophages divertStaphylococcus aureusdefenses against host lipids

“…This mechanism provides novel insights into the prevalence of hlb-converting prophages in clinical isolates and the role of the lipid environment in S. aureus adaptation to infection. Incorporation of PUFAs, such as C18:2, into PLs alters crucial functions that interact with the infecting host, including biofilm formation, secretion of virulence factors, and interference with immune defense (8,19,20,(54)(55)(56). Furthermore, C18:2 and sphingolipid metabolism are key pathways affected by S. aureus to decrease macrophage efficacy (57).…”

Two-Component Systems of S. aureus: Signaling and Sensing Mechanisms

“…Recently, excess levels of both external and cytoplasmic free fatty acids were proposed to modulate bacterial virulence factor production via SaeRS inhibition [ 77 , 78 ]. Unsaturated fatty acids are generally stronger inhibitors than saturated fatty acids [ 79 ]. Accordingly, deletion of respiratory dehydrogenase genes, which leads to altered NAD + /NADH ratios and free fatty acid accumulation, is accompanied by reduced SaeRS activity [ 80 ].…”

“…Accordingly, deletion of respiratory dehydrogenase genes, which leads to altered NAD + /NADH ratios and free fatty acid accumulation, is accompanied by reduced SaeRS activity [ 80 ]. Fatty acid sensitivity occurs independently of SaePQ but requires the native SaeS transmembrane [ 79 ]. Thus, SaeS probably integrates membrane-active signals to either increase (HPN1) or decrease (fatty acids) SaeS kinase activity.…”