Antibiotic That Inhibits the ATPase Activity of an ATP-Binding Cassette Transporter by Binding to a Remote Extracellular Site

• DOI: 10.1021/jacs.7b04726
• Publication Date: 2017-07-20T20:03:56Z
• Authors: Leigh M. Matano; Heidi G. Morris; Anthony R. Hesser; Sara E. S. Martin; Wonsik Lee; Tristan W. Owens; Emaline Laney; Hidemasa Nakaminami; David Hooper; Timothy C. Meredith; Suzanne Walker
• Keywords: Teichoic acid

Antibiotic-resistant strains of Staphylococcus aureus pose a major threat to human health and there is an ongoing need for new antibiotics treat resistant infections. In high throughput screen (HTS) 230 000 small molecules designed identify bioactive wall teichoic acid (WTA) inhibitors, we identified one hit, which was expanded through chemical synthesis into panel potent compounds. We showed that these compounds target TarG, the transmembrane component two-component ATP-binding cassette (ABC) transporter TarGH, exports WTA precursors cell surface attachment peptidoglycan. purified, first time, have reconstituted ATPase activity in proteoliposomes. this compound series inhibits TarH-catalyzed ATP hydrolysis even though binding site maps TarG near opposite side membrane. These are ABC inhibitors shown block by domain. The potential as therapeutic agents S. infections, purification will enable further development.