Evaluation of Enoyl-ACP Reductase (FabK) as a Narrow-Spectrum Drug Target.

ACS Infect Dis

Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Department of Translational Medical Sciences, Texas A&M Health Science Center, Houston, Texas 77030, United States.

Published: May 2024

, a pathobiont inhabiting the oral cavity, contributes to opportunistic diseases, such as periodontal diseases and gastrointestinal cancers, which involve microbiota imbalance. Broad-spectrum antimicrobial agents, while effective against infections, can exacerbate dysbiosis. This necessitates the discovery of more targeted narrow-spectrum antimicrobial agents. We therefore investigated the potential for the fusobacterial enoyl-ACP reductase II (ENR II) isoenzyme FabK (C4N14_ 04250) as a narrow-spectrum drug target. ENRs catalyze the rate-limiting step in the bacterial fatty acid synthesis pathway. Bioinformatics revealed that of the four distinct bacterial ENR isoforms, specifically encodes FabK. Genetic studies revealed that was indispensable for growth, as the gene could not be deleted, and silencing of its mRNA inhibited growth under the test conditions. Remarkably, exogenous fatty acids failed to rescue growth inhibition caused by the silencing of . Screening of synthetic phenylimidazole analogues of a known FabK inhibitor identified an inhibitor (i.e., 681) of FabK enzymatic activity and growth, with an IC of 2.1 μM (1.0 μg/mL) and a MIC of 0.4 μg/mL, respectively. Exogenous fatty acids did not attenuate the activity of 681 against . Furthermore, FabK was confirmed as the intracellular target of 681 based on the overexpression of FabK shifting MICs and 681-resistant mutants having amino acid substitutions in FabK or mutations in other genetic loci affecting fatty acid biosynthesis. 681 had minimal activity against a range of commensal flora, and it was less active against streptococci in physiologic fatty acids. Taken together, FabK is an essential enzyme that is amenable to drug targeting for the discovery and development of narrow-spectrum antimicrobial agents.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11091888PMC
http://dx.doi.org/10.1021/acsinfecdis.3c00710DOI Listing

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