The Fatty Acid Synthesis Protein Enoyl-ACP Reductase II (FabK) is a Target for Narrow-Spectrum Antibacterials for Clostridium difficile Infection
| Autor: | Xiaoqian Wu, Dianqing Sun, Kirk E. Hevener, Ravi K. R. Marreddy, Julian G Hurdle, Madhab Sapkota, Jesse A. Jones, Allan M. Prior |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
030106 microbiology Gut flora Reductase Crystallography X-Ray Article DNA Antisense Microbiology 03 medical and health sciences chemistry.chemical_compound Gene silencing Gene Silencing Gene Fatty acid synthesis chemistry.chemical_classification biology Clostridioides difficile Fatty Acids Clostridium difficile biology.organism_classification Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) Anti-Bacterial Agents Biosynthetic Pathways 030104 developmental biology Infectious Diseases Enzyme chemistry CRISPR-Cas Systems Growth inhibition |
| Zdroj: | ACS Infectious Diseases. 5:208-217 |
| ISSN: | 2373-8227 |
| DOI: | 10.1021/acsinfecdis.8b00205 |
| Popis: | 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: | OpenAIRE |
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