Dual inhibition of DNA polymerase PolC and protein tyrosine phosphatase CpsB uncovers a novel antibiotic target |
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| Authors: | Alistair J. Standish Angela A. Salim Robert J. Capon Renato Morona |
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| Affiliation: | 1. School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA 5005, Australia;2. Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland, Australia;1. Institute of Physical Chemistry, Polish Academy of Sciences, Warsaw, Poland;2. IK4CIDETEC, Sensors Unit, Materials Division, Parque tecnológico de San Sebastián, P° Miramón 196, Donostia San Sebastian 20009, Spain;3. Institute for Cellular and Molecular Biology, University of Texas, Austin, Texas 78712;4. Center for Systems and Synthetic Biology, University of Texas, Austin, Texas 78712;5. Department of Chemistry and Biochemistry, University of Texas, Austin, Texas 78712;1. Department of Pediatrics, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China;2. Department of Respiratory Medicine, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China;3. Department of Radiology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China;4. Department of Dermatology, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China |
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| Abstract: | ![]()
Increasing antibiotic resistance is making the identification of novel antimicrobial targets critical. Recently, we discovered an inhibitor of protein tyrosine phosphatase CpsB, fascioquinol E (FQE), which unexpectedly inhibited the growth of Gram-positive pathogens. CpsB is a member of the polymerase and histidinol phosphate phosphatase (PHP) domain family. Another member of this family found in a variety of Gram-positive pathogens is DNA polymerase PolC. We purified the PHP domain from PolC (PolCPHP), and showed that this competes away FQE inhibition of CpsB phosphatase activity. Furthermore, we showed that this domain hydrolyses the 5′-p-nitrophenyl ester of thymidine-5′-monophosphate (pNP-TMP), which has been used as a measure of exonuclease activity. Finally, we showed that FQE not only inhibits the phosphatase activity of CpsB, but also ability of PolCPHP to catalyse the hydrolysis of pNP-TMP. This suggests that PolC may be the essential target of FQE, and that the PHP domain may represent an as yet untapped target for the development of novel antibiotics. |
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