Small-Molecule Inhibition of the C. difficile FAS-II Enzyme, FabK, Results in Selective Activity

Jesse A. Jones, Allan M. Prior, Ravi K.R. Marreddy, Rebecca D. Wahrmund, Julian G. Hurdle, Dianqing Sun, Kirk Hevener

Research output: Contribution to journalArticle

Abstract

Clostridioides difficile infection (CDI) is a leading cause of significant morbidity, mortality, and healthcare-related costs in the United States. After standard therapy, recurrence rates remain high, and multiple recurrences are not uncommon. Causes include treatments employing broad-spectrum agents that disrupt the normal host microbiota, as well as treatment-resistant spore formation by C. difficile. Thus, novel druggable anti-C. difficile targets that promote narrow-spectrum eradication and inhibition of sporulation are desired. As a critical rate-limiting step within the FAS-II bacterial fatty acid synthesis pathway, which supplies precursory component phospholipids found in bacterial cytoplasmic and spore-mediated membranes, enoyl-acyl carrier protein (ACP) reductase II (FabK) represents such a target. FabK is essential in C. difficile (CdFabK) and is structurally and mechanistically distinct from other isozymes found in gut microbiota species, making CdFabK an attractive narrow-spectrum target. We report here the kinetic evaluation of CdFabK, the biochemical activity of a series of phenylimidazole analogues, and microbiological data suggesting these compounds' selective antibacterial activity against C. difficile versus several other prominent gut organisms. The compounds display promising, selective, low micromolar CdFabK inhibitory activity without significantly affecting the growth of other gut organisms, and the series prototype (1b) is shown to be competitive for the CdFabK cofactor and uncompetitive for the substrate. A series analogue (1g) shows maintained inhibitory activity while also possessing increased solubility. These findings represent the basis for future drug discovery efforts by characterizing the CdFabK enzyme while demonstrating its druggability and potential role as a narrow-spectrum antidifficile target.

Original languageEnglish (US)
JournalACS Chemical Biology
DOIs
StatePublished - Jan 1 2019

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Acyl Carrier Protein
Isoenzymes
Phospholipids
Oxidoreductases
Fatty Acids
Solubility
Bacterial Spores
Membranes
Recurrence
Molecules
Kinetics
Microbiota
Substrates
Enzymes
Drug Discovery
Spores
Health Care Costs
Costs
Morbidity
Mortality

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine

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Small-Molecule Inhibition of the C. difficile FAS-II Enzyme, FabK, Results in Selective Activity. / Jones, Jesse A.; Prior, Allan M.; Marreddy, Ravi K.R.; Wahrmund, Rebecca D.; Hurdle, Julian G.; Sun, Dianqing; Hevener, Kirk.

In: ACS Chemical Biology, 01.01.2019.

Research output: Contribution to journalArticle

Jones, Jesse A. ; Prior, Allan M. ; Marreddy, Ravi K.R. ; Wahrmund, Rebecca D. ; Hurdle, Julian G. ; Sun, Dianqing ; Hevener, Kirk. / Small-Molecule Inhibition of the C. difficile FAS-II Enzyme, FabK, Results in Selective Activity. In: ACS Chemical Biology. 2019.
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