Exogenous fatty acid metabolism in bacteria

Abstract

Bacterial type II fatty acid synthesis (FASII) is a target for novel antibiotic development. All bacteria encode for mechanisms to incorporate exogenous fatty acids, and some bacteria can use exogenous fatty acids to bypass FASII inhibition. Bacteria encode three different mechanisms for activating exogenous fatty acids for incorporation into phospholipid synthesis. Exogenous fatty acids are converted into acyl-CoA in Gammaproteobacteria such as E. coli. Acyl-CoA molecules constitute a separate pool from endogenously synthesized acyl-ACP. Acyl-CoA can be used for phospholipid synthesis or broken down by β-oxidation, but cannot be used for lipopolysaccharide synthesis. Exogenous fatty acids are converted into acyl-ACP in some Gram-negative bacteria. The resulting acyl-ACP undergoes the same fates as endogenously synthesized acyl-ACP. Exogenous fatty acids are converted into acyl-phosphates in Gram-positive bacteria, and can be used for phospholipid synthesis or become acyl-ACP. Only the order Lactobacillales can use exogenous fatty acids to bypass FASII inhibition. FASII shuts down completely in presence of exogenous fatty acids in Lactobacillales, allowing Lactobacillales to synthesize phospholipids entirely from exogenous fatty acids. Inhibition of FASII cannot be bypassed in other bacteria because FASII is only partially down-regulated in presence of exogenous fatty acid or FASII is required to synthesize essential metabolites such as β-hydroxyacyl-ACP. Certain selective pressures such as FASII inhibition or growth in biofilms can select for naturally occurring one step mutations that attenuate endogenous fatty acid synthesis. Although attempts have been made to estimate the natural prevalence of these mutants, culture-independent metagenomic methods would provide a better estimate.

Lipidomic and Ultrastructural Characterization of Cell Envelope ofStaphylococcus aureusGrown in the Presence of Human Serum

“…Branched-chain fatty acids (BCFAs) and straight-chain saturated fatty acids (SCFAs) comprise the entirety of the fatty acid composition of the organism in cells grown in laboratory media (6, 7). However, it has been increasingly recognized that host fatty acids, including straight-chain unsaturated fatty acids (SCUFAs), are utilized by pathogens and incorporated directly into phospholipid molecules, thereby saving the energy and carbon costs of de novo fatty acid biosynthesis by the type II fatty acid synthesis (FASII) pathway (8, 9). In S. aureus , the fatty acids are predominantly found ester-linked in the polar lipids of the organism, with major phospholipid species being phosphatidylglycerol (PG), lysyl-phosphatidylglycerol (LysylPG), and cardiolipin (CL), and major glycolipid species being diglucosyldiacylglycerol (DGDG) and monoglucosyldiacylglycerol (MGDG) (7, 10, 11).…”

A FASII inhibitor prevents staphylococcal evasion of daptomycin by inhibiting phospholipid decoy production

“…The release of membrane phospholipids in response to daptomycin occurs via an active process that requires de novo phospholipid biosynthesis [9]. Whilst S. aureus has an endogenous fatty acid biosynthetic pathway (FASII), it can also incorporate fatty acids from the host into membrane phospholipid production [21-24]. Therefore, it was hypothesised that host-derived fatty acids would contribute to the production of lipids required for daptomycin-induced phospholipid release.…”

“…Whilst platensimycin is unsuitable as a therapeutic drug due to poor pharmacological properties, the FabI inhibitor AFN-1252 shows more promising characteristics and a pro-drug variant is currently undergoing phase 2 clinical trials [18,19]. However, despite excellent in vitro activity, the therapeutic value of inhibitors of fatty acid synthesis as mono-therapeutic agents has attracted much debate [20,21]. Several bacteria, including S. aureus , can utilise fatty acids present in the host to generate phospholipids [21-24].…”

“…However, despite excellent in vitro activity, the therapeutic value of inhibitors of fatty acid synthesis as mono-therapeutic agents has attracted much debate [20,21]. Several bacteria, including S. aureus , can utilise fatty acids present in the host to generate phospholipids [21-24]. Although wild-type S. aureus strains cannot fully substitute exogenous fatty acids for endogenous fatty acids synthesised via FASII, there is evidence that some clinical isolates have acquired mutations that enable them to fully bypass endogenous fatty acid biosynthesis by utilising host-derived fatty acids [22,25,26].…”

“…Furthermore, in vitro experimentation suggests that the acquisition of such mutations is dependent upon the presence of host-associated fatty acids, which means that the frequency at which resistance to AFN-1252 emerges in vivo may have been under-estimated [25,26]. As such, the long-term viability of fatty acid synthesis inhibitors, such as AFN-1252, as mono-therapeutic antibacterial drugs is unclear and their ability to block daptomycin-induced phospholipid release in the presence of exogenous fatty acids undetermined [20,21].…”