Discovery of Prenyltransferase Inhibitors with in Vitro and in Vivo Antibacterial Activity

Junfeng Song, Satish R. Malwal, Noman Baig, Lici A. Schurig-Briccio, Zijun Gao, Girija S. Vaidya, Kailing Yang, Nader S. Abutaleb, Mohamed N. Seleem, Robert B. Gennis, Taras V. Pogorelov, Eric Oldfield, Xinxin Feng

Research output: Contribution to journalArticlepeer-review

Abstract

Cis-prenyltransferases such as undecaprenyl diphosphate synthase (UPPS) and decaprenyl diphosphate synthase (DPPS) are essential enzymes in bacteria and are involved in cell wall biosynthesis. UPPS and DPPS are absent in the human genome, so they are of interest as targets for antibiotic development. Here, we screened a library of 750 compounds from National Cancer Institute Diversity Set V for the inhibition of Mycobacterium tuberculosis DPPS and found 17 hits, and then IC50s were determined using dose-response curves. Compounds were tested for growth inhibition against a panel of bacteria, for in vivo activity in a Staphylococcus aureus/Caenorhabditis elegans model, and for mammalian cell toxicity. The most active DPPS inhibitor was the dicarboxylic acid redoxal (compound 10), which also inhibited undecaprenyl diphosphate synthase (UPPS) as well as farnesyl diphosphate synthase. 10 was active against S. aureus, Clostridiodes difficile, Bacillus anthracis Sterne, and Bacillus subtilis, and there was a 3.4-fold increase in IC50 on addition of a rescue agent, undecaprenyl monophosphate. We found that 10 was also a weak protonophore uncoupler, leading to the idea that it targets both isoprenoid biosynthesis and the proton motive force. In an S. aureus/C. elegans in vivo model, 10 reduced the S. aureus burden 3 times more effectively than did ampicillin.

Original languageEnglish (US)
Pages (from-to)2979-2993
Number of pages15
JournalACS Infectious Diseases
Volume6
Issue number11
DOIs
StatePublished - Nov 13 2020

Keywords

  • DPPS inhibitor
  • IC
  • S. aureus
  • antibiotics
  • cis-prenyltransferases
  • growth inhibition

ASJC Scopus subject areas

  • Infectious Diseases

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