TY - JOUR
T1 - Antibiotic That Inhibits the ATPase Activity of an ATP-Binding Cassette Transporter by Binding to a Remote Extracellular Site
AU - Matano, Leigh M.
AU - Morris, Heidi G.
AU - Hesser, Anthony R.
AU - Martin, Sara E.S.
AU - Lee, Wonsik
AU - Owens, Tristan W.
AU - Laney, Emaline
AU - Nakaminami, Hidemasa
AU - Hooper, David
AU - Meredith, Timothy C.
AU - Walker, Suzanne
N1 - Funding Information:
We thank the staff at ICCB-Longwood Screening Facility for help; the CETR DTR Core for toxicity testing; and Michael Cameron Drug Metabolism and Pharmacokinetics Core, Scripps Research Institute for the microsomal stability and solubility assays. This work was funded by NIH grants U19AI109764, P01AI08324 and fellowship F32GM117704 (S.E.S.M.), and NSF GRFP grant DGE1144152 (A.R.H.).
Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/8/9
Y1 - 2017/8/9
N2 - Antibiotic-resistant strains of Staphylococcus aureus pose a major threat to human health and there is an ongoing need for new antibiotics to treat resistant infections. In a high throughput screen (HTS) of 230 000 small molecules designed to identify bioactive wall teichoic acid (WTA) inhibitors, we identified one hit, which was expanded through chemical synthesis into a small panel of potent compounds. We showed that these compounds target TarG, the transmembrane component of the two-component ATP-binding cassette (ABC) transporter TarGH, which exports WTA precursors to the cell surface for attachment to peptidoglycan. We purified, for the first time, a WTA transporter and have reconstituted ATPase activity in proteoliposomes. We showed that this new compound series inhibits TarH-catalyzed ATP hydrolysis even though the binding site maps to TarG near the opposite side of the membrane. These are the first ABC transporter inhibitors shown to block ATPase activity by binding to the transmembrane domain. The compounds have potential as therapeutic agents to treat S. aureus infections, and purification of the transmembrane transporter will enable further development.
AB - Antibiotic-resistant strains of Staphylococcus aureus pose a major threat to human health and there is an ongoing need for new antibiotics to treat resistant infections. In a high throughput screen (HTS) of 230 000 small molecules designed to identify bioactive wall teichoic acid (WTA) inhibitors, we identified one hit, which was expanded through chemical synthesis into a small panel of potent compounds. We showed that these compounds target TarG, the transmembrane component of the two-component ATP-binding cassette (ABC) transporter TarGH, which exports WTA precursors to the cell surface for attachment to peptidoglycan. We purified, for the first time, a WTA transporter and have reconstituted ATPase activity in proteoliposomes. We showed that this new compound series inhibits TarH-catalyzed ATP hydrolysis even though the binding site maps to TarG near the opposite side of the membrane. These are the first ABC transporter inhibitors shown to block ATPase activity by binding to the transmembrane domain. The compounds have potential as therapeutic agents to treat S. aureus infections, and purification of the transmembrane transporter will enable further development.
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U2 - 10.1021/jacs.7b04726
DO - 10.1021/jacs.7b04726
M3 - Article
C2 - 28727445
AN - SCOPUS:85027195387
SN - 0002-7863
VL - 139
SP - 10597
EP - 10600
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 31
ER -