Bacterial fatty acid metabolism in modern antibiotic discovery

Abstract

Bacterial fatty acid synthesis is essential for many pathogens and different from the mammalian counterpart. These features make bacterial fatty acid synthesis a desirable target for antibiotic discovery. The structural divergence of the conserved enzymes and the presence of different isozymes catalyzing the same reactions in the pathway make bacterial fatty acid synthesis a narrow spectrum target rather than the traditional broad spectrum target. Furthermore, bacterial fatty acid synthesis inhibitors are single-targeting, rather than multi-targeting like traditional monotherapeutic, broad-spectrum antibiotics. The single-targeting nature of bacterial fatty acid synthesis inhibitors makes overcoming fast-developing, target-based resistance a necessary consideration for antibiotic development. Target-based resistance can be overcome through multi-targeting inhibitors, a cocktail of single-targeting inhibitors, or by making the single targeting inhibitor sufficiently high affinity through a pathogen selective approach such that target-based mutants are still susceptible to therapeutic concentrations of drug. Many of the pathogens requiring new antibiotic treatment options encode for essential bacterial fatty acid synthesis enzymes. This review will evaluate the most promising targets in bacterial fatty acid metabolism for antibiotic therapeutics development and review the potential and challenges in advancing each of these targets to the clinic and circumventing target-based resistance.

Isotopically Labeled Desthiobiotin Azide (isoDTB) Tags Enable Global Profiling of the Bacterial Cysteinome

“…Next, we looked at the binding of our covalent ligands to aselection of ligandable cysteines in more detail (Figure 5b). While the most ligandable cysteines tend to be engaged by the most promiscuous compounds,t here is clear evidence for more specific interactions between less ligandable cysteines with more selective compounds.F or example,t he active site residue C112 of FabH (UniProt code Q2FZS0), an essential enzyme in fatty acid synthesis, [20] is exclusively targeted by three compounds of tempered promiscuity (EN002, EN204 and EN208,F igure 5b). This residue has previously been shown to be covalently modified for example,b yt he inhibitors 4,5-dichloro-1,2-dithiol-3-oneand cerulenin.…”

Exogenous fatty acid metabolism in bacteria

“…Determining the rate and mechanism of resistance mutations against an antibiotic candidate by plating the susceptible bacteria against the antibiotic candidate is a well described and routine step in antibiotic discovery [4,92,93]. Resistant mutants against single-target antibiotics are practically guaranteed to occur and are often used to determine/validate the mechanism of the antibiotic.…”

“…Significant reservoirs of such mutants can accumulate in environmental S. aureus populations, unlike the fatty acid auxotrophs which can only grow in environments with sufficient exogenous fatty acids. Whether single step mutations leading to high level resistance affect the efficacy of single-target antibiotics is under active discussion and play into the strategy of developing novel antibiotics [4,92,96]. Well-designed and comprehensive experiments characterizing the fitness consequences of these mutations will be essential to interpret their importance to successful antibiotic therapy.…”

“…1) [2]. Due to differences between FASII and the monofunctional mammalian type I fatty acid synthase [3], targeting FASII enzymes for novel antibiotic therapeutics is an active area of research [4–7]. However, all bacteria characterized to date can assimilate exogenous fatty acids [8–12], but only some species can bypass inhibition of FASII by incorporating exogenous fatty acids [13].…”

Isotopically Labeled Desthiobiotin Azide (isoDTB) Tags Enable Global Profiling of the Bacterial Cysteinome

“…While the most ligandable cysteines tend to be engaged by the most promiscuous compounds, there is clear evidence for more specific interactions between less ligandable cysteines with more selective compounds. For example, the active site residue C112 of FabH (UniProt code Q2FZS0), an essential enzyme in fatty acid synthesis, is exclusively targeted by three compounds of tempered promiscuity ( EN002 , EN204 and EN208 , Figure b). This residue has previously been shown to be covalently modified for example, by the inhibitors 4,5‐dichloro‐1,2‐dithiol‐3‐one and cerulenin .…”