Identification and analysis of small molecule inhibitors of FosB from Staphylococcus aureus

Skye Travis, Keith D. Green, Nishad Thamban Chandrika, Allan H. Pang, Patrick A. Frantom, Oleg V. Tsodikov, Sylvie Garneau-Tsodikova, Matthew K. Thompson

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Antimicrobial resistance (AMR) poses a significant threat to human health around the world. Though bacterial pathogens can develop resistance through a variety of mechanisms, one of the most prevalent is the production of antibiotic-modifying enzymes like FosB, a Mn2+-dependent l-cysteine or bacillithiol (BSH) transferase that inactivates the antibiotic fosfomycin. FosB enzymes are found in pathogens such as Staphylococcus aureus, one of the leading pathogens in deaths associated with AMR. fosB gene knockout experiments establish FosB as an attractive drug target, showing that the minimum inhibitory concentration (MIC) of fosfomycin is greatly reduced upon removal of the enzyme. Herein, we have identified eight potential inhibitors of the FosB enzyme from S. aureus by applying high-throughput in silico screening of the ZINC15 database with structural similarity to phosphonoformate, a known FosB inhibitor. In addition, we have obtained crystal structures of FosB complexes to each compound. Furthermore, we have kinetically characterized the compounds with respect to inhibition of FosB. Finally, we have performed synergy assays to determine if any of the new compounds lower the MIC of fosfomycin in S. aureus. Our results will inform future studies on inhibitor design for the FosB enzymes.

Original languageEnglish
Pages (from-to)947-956
Number of pages10
JournalRSC Medicinal Chemistry
Issue number5
StatePublished - Apr 24 2023

Bibliographical note

Publisher Copyright:
© The Royal Society of Chemistry 2023.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry


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