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

DIR@IMTECH: CSIR-Institute of Microbial Technology

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Title Search for non-lactam inhibitors of mtb β-lactamase led to its open shape in apo state: new concept for antibiotic design
 
Creator Sagar, Amin
Haleem, Nazia
Bashir, Yaawar Mir
Ashish, .
 
Subject QR Microbiology
 
Description 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 of gyration of 2.3 nm compared to 1.9 nm of crystal structures) in solution; (2) closed shape similar to observed crystal structure(s) in presence of effective inhibitor; and (3) a closed shape which opens up when a hydrolysable inhibitor is present in solution. New BlaC inhibitors were: 1-(4-(pyridin-3-yl)-thiazol-2-ylamino)-2-(7,8,9-triaza-bicyclo[4.3.0]nona-1(6),2,4,8-tetraen-7-yl)-ethanone; 8-butyl-3-((5-(pyridin-2-yl)-4H-1,2,4-triazol-3-ylamino)-formyl)-8-aza-bicyclo[4.3.0]nona-1(6),2,4-triene-7,9-dione; 1-(3-((5-(5-bromo-thiophen-2-yl)-1,3,4-oxadiazol-2-yl)-methoxy)-phenyl)-1H-1,2,3,4-tetraazole; and 1-(2,3-dimethyl-phenylamino)-2-(2-(1-(2-methoxy-5-methyl-phenyl)-1H-1,2,3,4-tetraazol-5-ylsulfanyl)-acetylamino)-ethanone. The open-close shape of BlaC questions the physiological significance of the closed shape known for BlaC-/+ inhibitors and paves new path for structure aided design of novel inhibitors.
 
Publisher Nature Publishing Group
 
Date 2017
 
Type Article
PeerReviewed
 
Relation http://dx.doi.org/10.1038/s41598-017-06023-3
http://crdd.osdd.net/open/2061/
 
Identifier Sagar, Amin and Haleem, Nazia and Bashir, Yaawar Mir and Ashish, . (2017) Search for non-lactam inhibitors of mtb β-lactamase led to its open shape in apo state: new concept for antibiotic design. Scientific Reports, 7 (1). ISSN 2045-2322