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

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 Charles Meredith, Suzanne Walker

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)10597-10600
Number of pages4
JournalJournal of the American Chemical Society
Volume139
Issue number31
DOIs
StatePublished - Aug 9 2017

Fingerprint

Teichoic Acids
ATP-Binding Cassette Transporters
Adenosinetriphosphate
Antibiotics
Adenosine Triphosphatases
Anti-Bacterial Agents
Acids
Staphylococcus aureus
Peptidoglycan
Binding sites
Infection
Purification
Hydrolysis
Adenosine Triphosphate
Binding Sites
Throughput
Health
Membranes
Molecules
Therapeutics

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Matano, L. M., Morris, H. G., Hesser, A. R., Martin, S. E. S., Lee, W., Owens, T. W., ... Walker, S. (2017). Antibiotic That Inhibits the ATPase Activity of an ATP-Binding Cassette Transporter by Binding to a Remote Extracellular Site. Journal of the American Chemical Society, 139(31), 10597-10600. https://doi.org/10.1021/jacs.7b04726
Matano, Leigh M. ; Morris, Heidi G. ; Hesser, Anthony R. ; Martin, Sara E.S. ; Lee, Wonsik ; Owens, Tristan W. ; Laney, Emaline ; Nakaminami, Hidemasa ; Hooper, David ; Meredith, Timothy Charles ; Walker, Suzanne. / Antibiotic That Inhibits the ATPase Activity of an ATP-Binding Cassette Transporter by Binding to a Remote Extracellular Site. In: Journal of the American Chemical Society. 2017 ; Vol. 139, No. 31. pp. 10597-10600.
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Matano, LM, Morris, HG, Hesser, AR, Martin, SES, Lee, W, Owens, TW, Laney, E, Nakaminami, H, Hooper, D, Meredith, TC & Walker, S 2017, 'Antibiotic That Inhibits the ATPase Activity of an ATP-Binding Cassette Transporter by Binding to a Remote Extracellular Site', Journal of the American Chemical Society, vol. 139, no. 31, pp. 10597-10600. https://doi.org/10.1021/jacs.7b04726

Antibiotic That Inhibits the ATPase Activity of an ATP-Binding Cassette Transporter by Binding to a Remote Extracellular Site. / Matano, Leigh M.; Morris, Heidi G.; Hesser, Anthony R.; Martin, Sara E.S.; Lee, Wonsik; Owens, Tristan W.; Laney, Emaline; Nakaminami, Hidemasa; Hooper, David; Meredith, Timothy Charles; Walker, Suzanne.

In: Journal of the American Chemical Society, Vol. 139, No. 31, 09.08.2017, p. 10597-10600.

Research output: Contribution to journalArticle

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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 Charles

AU - Walker, Suzanne

PY - 2017/8/9

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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.

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