Bis(benzoyl) phosphate inactivators of beta-lactamase C from Mtb.

ABSTRACT: The class A ?-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 ?-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 ?p?=?-0.27 to 0.78 for electronic and ??=?-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.

SUBMITTER: White DS 

PROVIDER: S-EPMC7654513 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature