title: Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase.
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.
authors.affiliation: Department of Molecular Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Molecular Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
authors.forename: Hongchuan
authors.initials: H
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
authors.forename: Kongkai
authors.initials: K
authors.lastname: Zhu
authors.affiliation: Department of Molecular Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
authors.forename: Shouzhe
authors.initials: S
authors.lastname: Gong
authors.affiliation: 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.
authors.forename: Shaynoor
authors.initials: S
authors.lastname: Dramsi
authors.affiliation: Department of Microbiology, The University of Chicago, Chicago, IL 60637;
authors.forename: Ya-Ting
authors.initials: YT
authors.lastname: Wang
authors.affiliation: Department of Molecular Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
authors.forename: Jiafei
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Molecular Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
authors.forename: Feifei
authors.initials: F
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
authors.forename: Ruihan
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Molecular Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
authors.forename: Lefu
authors.initials: L
authors.lastname: Lan
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Microbiology, The University of Chicago, Chicago, IL 60637; oschnee@bsd.uchicago.edu cluo@simm.ac.cn yangcg@simm.ac.cn.
authors.forename: Olaf
authors.initials: O
authors.lastname: Schneewind
authors.affiliation: 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.
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.affiliation: 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.
authors.forename: Cai-Guang
authors.initials: CG
authors.lastname: Yang
mesh_terms: D019881:Aminoacyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D055162:Biocatalysis / Q000187:drug effects; D003546:Cysteine Endopeptidases; D005260:Female; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D010455:Peptides / Q000378:metabolism; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology*; D013297:Streptococcus pyogenes / Q000187:drug effects / Q000201:enzymology; D013830:Thiadiazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D010455:Peptides; D011480:Protease Inhibitors; D054852:Small Molecule Libraries; D013830:Thiadiazoles; D019881:Aminoacyltransferases; C120542:sortase A; D003546:Cysteine Endopeptidases
keywords: LPXTG motif; antivirulence; computational screening; nosocomial infection