2. Academic Validation
  3. Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase

Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase

  • Proc Natl Acad Sci U S A. 2014 Sep 16;111(37):13517-22. doi: 10.1073/pnas.1408601111.
Jie Zhang 1,  Hongchuan Liu 1,  Kongkai Zhu 2,  Shouzhe Gong 1,  Shaynoor Dramsi 3,  Ya-Ting Wang 4,  Jiafei Li 1,  Feifei Chen 1,  Ruihan Zhang 2,  Lu Zhou 5,  Lefu Lan 1,  Hualiang Jiang 2,  Olaf Schneewind 6,  Cheng Luo 7,  Cai-Guang Yang 8
Affiliations

Affiliations

  • 1 Department of Molecular Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
  • 3 Department of Microbiology, The University of Chicago, Chicago, IL 60637; Institut Pasteur, Unité de Biologie des Bactéries Pathogènes à Gram-Positif, Centre National de la Recherche Scientifique Équipe de Recherche Labellisée 3526, 75724 Paris, France; and.
  • 4 Department of Microbiology, The University of Chicago, Chicago, IL 60637;
  • 5 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 6 Department of Microbiology, The University of Chicago, Chicago, IL 60637; oschnee@bsd.uchicago.edu cluo@simm.ac.cn yangcg@simm.ac.cn.
  • 7 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; oschnee@bsd.uchicago.edu cluo@simm.ac.cn yangcg@simm.ac.cn.
  • 8 Department of Molecular Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; oschnee@bsd.uchicago.edu cluo@simm.ac.cn yangcg@simm.ac.cn.
PMID: 25197057 DOI: 10.1073/pnas.1408601111
Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is the most frequent cause of hospital-acquired Infection, which manifests as surgical site infections, bacteremia, and sepsis. Due to drug-resistance, prophylaxis of MRSA Infection with Antibiotics frequently fails or incites nosocomial diseases such as Clostridium difficile Infection. Sortase A is a transpeptidase that anchors surface proteins in the envelope of S. aureus, and sortase mutants are unable to cause bacteremia or sepsis in mice. Here we used virtual screening and optimization of inhibitor structure to identify 3-(4-pyridinyl)-6-(2-sodiumsulfonatephenyl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole and related compounds, which block sortase activity in vitro and in vivo. Sortase inhibitors do not affect in vitro staphylococcal growth yet protect mice against lethal S. aureus bacteremia. Thus, sortase inhibitors may be useful as antiinfective therapy to prevent hospital-acquired S. aureus Infection in high-risk patients without the side effects of Antibiotics.

Keywords

LPXTG motif; antivirulence; computational screening; nosocomial infection.

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