Bis(benzoyl) phosphate inactivators of beta-lactamase C from Mtb |
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| Institution: | 1. Washington State University, Department of Chemistry, Pullman, WA 99164-6340, United States;2. Washington State University, Tissue Imaging and Proteomics Laboratory, Pullman, WA 99164-4630, United States;1. Solar Energy Research Institute of Singapore, National University of Singapore, Engineering Drive 1, S117574 Singapore, Singapore;2. Department of Chemical and Biomolecular Engineering, National University of Singapore, 117576 Singapore, Singapore;1. Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon 97331, United States;2. Proteomics Facility, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, United States;3. Department of Biochemistry & Biophysics, Oregon State University, Corvallis, Oregon 97331, United States;1. Department of Chemical Physics, Weizmann Institute of Science, 76100 Rehovot, Israel;2. Department of Electronic Science, Xiamen University, Xiamen 361005, China;3. Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306, USA |
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| Abstract: | The class A β-lactamase BlaC is a cell surface expressed serine hydrolase of Mycobacterium tuberculosis (Mtb), one of the causative agents for Tuberculosis in humans. Mtb has demonstrated increased susceptibility to β-lactam antibiotics upon inactivation of BlaC; thus, making BlaC a rational enzyme target for therapeutic agents. Herein, we present the synthesis and structure-activity-relationship data for the 1st-generation library of bis(benzoyl) phosphates (1–10). Substituent effects ranged from σp = ?0.27 to 0.78 for electronic and π = ?0.41 to 1.98 for hydrophobic parameters. Compounds 1, 4 and 5 demonstrated the greatest inhibitory potency against BlaC in a time-dependent manner (kobs = 0.212, 0.324, and 0.450 mn?1 respectively). Combined crystal structure data and mass spectrometric analysis of a tryptic digest for BlaC inactivated with 4 provided evidence that the mechanism of inactivation by this bis(benzoyl) phosphate scaffold occurs via phosphorylation of the active-site Ser-70, ultimately leading to an aged form of the enzyme. |
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| Keywords: | Beta-lactamase BlaC Tuberculosis Inhibition Phosphorylation |
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