Search for non-lactam inhibitors of mtb β-lactamase led to its open shape in apo state: new concept for antibiotic design.

ABSTRACT: Mtb β-lactamase (BlaC) is extremely efficient in hydrolyzing ß-lactam antibiotics which renders/leads to protection and/or resistance to this bug. There is a compelling need to develop new non-lactam inhibitors which can bind and inhibit BlaC, but cannot be hydrolyzed, thus neutralizing this survival mechanism of Mtb. Using the crystal structure of BlaC we screened 750000 purchasable compounds from ZINC Database for their theoretical affinity to the enzyme's active site. 32 of the best hits of the compounds having tetra-, tri- and thiadi-azole moiety were tested in vitro, and 4 efficiently inhibited the enzymatic activity of recombinant BlaC. Characterization of the shape of BlaC-/+ inhibitors by small angle X-ray scattering (SAXS) brought forth that BlaC adopts: (1) an open shape (radius

SUBMITTER: Sagar A 

PROVIDER: S-EPMC5524718 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature