The Fatty Acid Synthesis Protein Enoyl-ACP Reductase II (FabK) is a Target for Narrow-Spectrum Antibacterials for Clostridium difficile Infection.

Autor:	Marreddy RKR; Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology , Texas A&M Health Science Center , 2121 West Holcombe Boulevard , Houston , Texas 77030 , United States., Wu X; Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology , Texas A&M Health Science Center , 2121 West Holcombe Boulevard , Houston , Texas 77030 , United States., Sapkota M; Department of Biology , University of Texas Arlington , 701 West Nedderman Drive , Arlington , Texas 76019 , United States., Prior AM; Department of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy , University of Hawaii at Hilo , 34 Rainbow Drive , Hilo , Hawaii 96720 , United States., Jones JA; Department of Pharmaceutical Sciences, College of Pharmacy , University of Tennessee Health Science Center , 881 Madison Avenue , Memphis , Tennessee 38105 , United States., Sun D; Department of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy , University of Hawaii at Hilo , 34 Rainbow Drive , Hilo , Hawaii 96720 , United States., Hevener KE; Department of Pharmaceutical Sciences, College of Pharmacy , University of Tennessee Health Science Center , 881 Madison Avenue , Memphis , Tennessee 38105 , United States., Hurdle JG; Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology , Texas A&M Health Science Center , 2121 West Holcombe Boulevard , Houston , Texas 77030 , United States.
Jazyk:	angličtina
Zdroj:	ACS infectious diseases [ACS Infect Dis] 2019 Feb 08; Vol. 5 (2), pp. 208-217. Date of Electronic Publication: 2018 Dec 13.
DOI:	10.1021/acsinfecdis.8b00205
Abstrakt:	Clostridium difficile infection (CDI) is an antibiotic-induced microbiota shift disease of the large bowel. While there is a need for narrow-spectrum CDI antibiotics, it is unclear which cellular proteins are appropriate drug targets to specifically inhibit C. difficile. We evaluated the enoyl-acyl carrier protein (ACP) reductase II (FabK), which catalyzes the final step of bacterial fatty acid biosynthesis. Bioinformatics showed that C. difficile uses FabK as its sole enoyl-ACP reductase, unlike several major microbiota species. The essentiality of fabK for C. difficile growth was confirmed by failure to delete this gene using ClosTron mutagenesis and by growth inhibition upon gene silencing with CRISPR interference antisense to fabK transcription or by blocking protein translation. Inhibition of C. difficile's FASII pathway could not be circumvented by supply of exogenous fatty acids, either during fabK's gene silencing or upon inhibition of the enzyme with a phenylimidazole-derived inhibitor (1). The inability of fatty acids to bypass FASII inhibition is likely due to the function of the transcriptional repressor FapR. Inhibition of FabK also inhibited spore formation, reflecting the enzyme's role in de novo fatty acid biosynthesis for the formation of spore membrane lipids. Compound 1 did not inhibit growth of key microbiota species. These findings suggest that C. difficile FabK is a druggable target for discovering narrow-spectrum anti- C. difficile drugs that treat CDI but avoid collateral damage to the gut microbiota.
Databáze:	MEDLINE
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