Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase

Jie Zhang (1) , Hongchuan Liu (1) , Kongkai Zhu (1) , Shouzhe Gong (1) , Shaynoor Dramsi (2, 3) , Ya-Ting Wang (2) , Jiafei Li (1) , Feifei Chen (1) , Ruihan Zhang (1) , Lu Zhou (4) , Lefu Lan (1) , Hualiang Jiang (1) , Olaf Schneewind (2) , Cheng Luo (1) , Cai-Guang Yang (1)

1 Shanghai Institute of Materia Medica - Chinese Academy of Sciences [Shanghai]
2 University of Chicago
3 Biologie des Bactéries pathogènes à Gram-positif
4 Fudan University [Shanghai]

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: nosocomial infection; LPXTG motif; antivirulence; computational screening

Domains: Life Sciences [q-bio]

Jie Zhang, Hongchuan Liu, Kongkai Zhu, Shouzhe Gong, Shaynoor Dramsi, et al.. Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase. Proceedings of the National Academy of Sciences of the United States of America, 2014, 111 (37), pp.13517-13522. ⟨10.1073/pnas.1408601111⟩. ⟨pasteur-03262305⟩