2. Academic Validation
  3. Mechanistic Studies and In Vivo Efficacy of an Oxadiazole-Containing Antibiotic

Mechanistic Studies and In Vivo Efficacy of an Oxadiazole-Containing Antibiotic

  • J Med Chem. 2022 May 12;65(9):6612-6630. doi: 10.1021/acs.jmedchem.1c02034.
George A Naclerio 1,  Nader S Abutaleb 2 3,  Kenneth I Onyedibe 1 4,  Caroline Karanja 1,  Hassan E Eldesouky 2 3,  Hsin-Wen Liang 2,  Alexandra Dieterly 3,  Uma K Aryal 3 5,  Tiffany Lyle 3 6,  Mohamed N Seleem 2 3 7,  Herman O Sintim 1 4
Affiliations

Affiliations

  • 1 Chemistry Department, Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States.
  • 2 Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24060, United States.
  • 3 Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana 47907, United States.
  • 4 Purdue Institute of Inflammation, Immunology, and Infectious Disease, Purdue University, West Lafayette, Indiana 47907, United States.
  • 5 Purdue Proteomics Facility, Bindley Bioscience Center, Purdue University, West Lafayette, Indiana 47907, United States.
  • 6 Center for Comparative Translational Research, Purdue University, West Lafayette, Indiana 47907, United States.
  • 7 Center for Emerging, Zoonotic and Arthropod-borne Pathogens, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, United States.
PMID: 35482444 DOI: 10.1021/acs.jmedchem.1c02034
Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) infections are still difficult to treat, despite the availability of many FDA-approved Antibiotics. Thus, new compound scaffolds are still needed to treat MRSA. The oxadiazole-containing compound, HSGN-94, has been shown to reduce lipoteichoic acid (LTA) in S. aureus, but the mechanism that accounts for LTA biosynthesis inhibition remains uncharacterized. Herein, we report the elucidation of the mechanism by which HSGN-94 inhibits LTA biosynthesis via utilization of global proteomics, activity-based protein profiling, and lipid analysis via multiple reaction monitoring (MRM). Our data suggest that HSGN-94 inhibits LTA biosynthesis via direct binding to PgcA and downregulation of PgsA. We further show that HSGN-94 reduces the MRSA load in skin Infection (mouse) and decreases pro-inflammatory cytokines in MRSA-infected wounds. Collectively, HSGN-94 merits further consideration as a potential drug for staphylococcal infections.

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