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 thi...

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Autores principales:	Amin Sagar, Nazia Haleem, Yaawar Mir Bashir, Ashish
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b4ce3fcb17334e4faf9e86a12a35893b
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spelling	oai:doaj.org-article:b4ce3fcb17334e4faf9e86a12a35893b2021-12-02T15:05:51ZSearch for non-lactam inhibitors of mtb β-lactamase led to its open shape in apo state: new concept for antibiotic design10.1038/s41598-017-06023-32045-2322https://doaj.org/article/b4ce3fcb17334e4faf9e86a12a35893b2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06023-3https://doaj.org/toc/2045-2322Abstract 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.Amin SagarNazia HaleemYaawar Mir BashirAshishNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Amin Sagar Nazia Haleem Yaawar Mir Bashir Ashish Search for non-lactam inhibitors of mtb β-lactamase led to its open shape in apo state: new concept for antibiotic design
description	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 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.
format	article
author	Amin Sagar Nazia Haleem Yaawar Mir Bashir Ashish
author_facet	Amin Sagar Nazia Haleem Yaawar Mir Bashir Ashish
author_sort	Amin Sagar
title	Search for non-lactam inhibitors of mtb β-lactamase led to its open shape in apo state: new concept for antibiotic design
title_short	Search for non-lactam inhibitors of mtb β-lactamase led to its open shape in apo state: new concept for antibiotic design
title_full	Search for non-lactam inhibitors of mtb β-lactamase led to its open shape in apo state: new concept for antibiotic design
title_fullStr	Search for non-lactam inhibitors of mtb β-lactamase led to its open shape in apo state: new concept for antibiotic design
title_full_unstemmed	Search for non-lactam inhibitors of mtb β-lactamase led to its open shape in apo state: new concept for antibiotic design
title_sort	search for non-lactam inhibitors of mtb β-lactamase led to its open shape in apo state: new concept for antibiotic design
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/b4ce3fcb17334e4faf9e86a12a35893b
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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

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