Cargando…

Towards discovery of inhibitors of the undecaprenyl-pyrophosphate phosphatase BacA by virtual high-throughput screening

Increasing resistance to common antibiotics is becoming a major challenge that requires the development of new antibacterial agents. Peptidoglycan is an essential heteropolymer of the bacterial envelope that ensures the integrity and shape of all bacteria and is also an important target for antibiot...

Descripción completa

Detalles Bibliográficos
Autores principales: Jukič, Marko, Auger, Rodolphe, Folcher, Victor, Proj, Matic, Barreteau, Hélène, Gobec, Stanislav, Touzé, Thierry
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Research Network of Computational and Structural Biotechnology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9127117/
https://www.ncbi.nlm.nih.gov/pubmed/35664230
http://dx.doi.org/10.1016/j.csbj.2022.05.010
_version_ 1784712277502459904
author Jukič, Marko
Auger, Rodolphe
Folcher, Victor
Proj, Matic
Barreteau, Hélène
Gobec, Stanislav
Touzé, Thierry
author_facet Jukič, Marko
Auger, Rodolphe
Folcher, Victor
Proj, Matic
Barreteau, Hélène
Gobec, Stanislav
Touzé, Thierry
author_sort Jukič, Marko
collection PubMed
description Increasing resistance to common antibiotics is becoming a major challenge that requires the development of new antibacterial agents. Peptidoglycan is an essential heteropolymer of the bacterial envelope that ensures the integrity and shape of all bacteria and is also an important target for antibiotics. The biosynthesis of peptidoglycan depends on a lipid carrier, undecaprenyl phosphate. As a byproduct of peptidoglycan polymerization, the lipid carrier is released as undecaprenyl pyrophosphate, which must be recycled to allow new polymerization cycles. To this end, it undergoes a dephosphorylation process catalyzed by the membrane phosphatase BacA, which is specific and highly conserved in bacteria. In the present study, we identified small molecules displaying inhibitory potency towards BacA. We began by preparing a commercial compound library, followed by high-throughput virtual screening by ensemble docking using the 3D structure of BacA and molecular dynamics snapshots to account for the flexibility of the protein. Of 83 compounds computationally selected and tested in a biochemical assay, one sulfamoylthiophene molecule showed significant inhibition of the undecaprenyl pyrophosphate dephosphorylation activity catalyzed by BacA. Subsequently, an additional 33 scaffold analogs were selected and acquired, of which 6 compounds exhibited BacA inhibition. The IC(50) values of these compounds ranged from 42 to 366 μM. In addition, significant antibacterial activity against Escherichia coli was observed in TolC/PAP2-depleted strains. We believe that the overall strategy followed in this study and the identified class of inhibitors provide a solid foundation for the further development of potent BacA-targeted inhibitors and the discovery of novel antibacterial compounds.
format Online
Article
Text
id pubmed-9127117
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Research Network of Computational and Structural Biotechnology
record_format MEDLINE/PubMed
spelling pubmed-91271172022-06-04 Towards discovery of inhibitors of the undecaprenyl-pyrophosphate phosphatase BacA by virtual high-throughput screening Jukič, Marko Auger, Rodolphe Folcher, Victor Proj, Matic Barreteau, Hélène Gobec, Stanislav Touzé, Thierry Comput Struct Biotechnol J Research Article Increasing resistance to common antibiotics is becoming a major challenge that requires the development of new antibacterial agents. Peptidoglycan is an essential heteropolymer of the bacterial envelope that ensures the integrity and shape of all bacteria and is also an important target for antibiotics. The biosynthesis of peptidoglycan depends on a lipid carrier, undecaprenyl phosphate. As a byproduct of peptidoglycan polymerization, the lipid carrier is released as undecaprenyl pyrophosphate, which must be recycled to allow new polymerization cycles. To this end, it undergoes a dephosphorylation process catalyzed by the membrane phosphatase BacA, which is specific and highly conserved in bacteria. In the present study, we identified small molecules displaying inhibitory potency towards BacA. We began by preparing a commercial compound library, followed by high-throughput virtual screening by ensemble docking using the 3D structure of BacA and molecular dynamics snapshots to account for the flexibility of the protein. Of 83 compounds computationally selected and tested in a biochemical assay, one sulfamoylthiophene molecule showed significant inhibition of the undecaprenyl pyrophosphate dephosphorylation activity catalyzed by BacA. Subsequently, an additional 33 scaffold analogs were selected and acquired, of which 6 compounds exhibited BacA inhibition. The IC(50) values of these compounds ranged from 42 to 366 μM. In addition, significant antibacterial activity against Escherichia coli was observed in TolC/PAP2-depleted strains. We believe that the overall strategy followed in this study and the identified class of inhibitors provide a solid foundation for the further development of potent BacA-targeted inhibitors and the discovery of novel antibacterial compounds. Research Network of Computational and Structural Biotechnology 2022-05-11 /pmc/articles/PMC9127117/ /pubmed/35664230 http://dx.doi.org/10.1016/j.csbj.2022.05.010 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Jukič, Marko
Auger, Rodolphe
Folcher, Victor
Proj, Matic
Barreteau, Hélène
Gobec, Stanislav
Touzé, Thierry
Towards discovery of inhibitors of the undecaprenyl-pyrophosphate phosphatase BacA by virtual high-throughput screening
title Towards discovery of inhibitors of the undecaprenyl-pyrophosphate phosphatase BacA by virtual high-throughput screening
title_full Towards discovery of inhibitors of the undecaprenyl-pyrophosphate phosphatase BacA by virtual high-throughput screening
title_fullStr Towards discovery of inhibitors of the undecaprenyl-pyrophosphate phosphatase BacA by virtual high-throughput screening
title_full_unstemmed Towards discovery of inhibitors of the undecaprenyl-pyrophosphate phosphatase BacA by virtual high-throughput screening
title_short Towards discovery of inhibitors of the undecaprenyl-pyrophosphate phosphatase BacA by virtual high-throughput screening
title_sort towards discovery of inhibitors of the undecaprenyl-pyrophosphate phosphatase baca by virtual high-throughput screening
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9127117/
https://www.ncbi.nlm.nih.gov/pubmed/35664230
http://dx.doi.org/10.1016/j.csbj.2022.05.010
work_keys_str_mv AT jukicmarko towardsdiscoveryofinhibitorsoftheundecaprenylpyrophosphatephosphatasebacabyvirtualhighthroughputscreening
AT augerrodolphe towardsdiscoveryofinhibitorsoftheundecaprenylpyrophosphatephosphatasebacabyvirtualhighthroughputscreening
AT folchervictor towardsdiscoveryofinhibitorsoftheundecaprenylpyrophosphatephosphatasebacabyvirtualhighthroughputscreening
AT projmatic towardsdiscoveryofinhibitorsoftheundecaprenylpyrophosphatephosphatasebacabyvirtualhighthroughputscreening
AT barreteauhelene towardsdiscoveryofinhibitorsoftheundecaprenylpyrophosphatephosphatasebacabyvirtualhighthroughputscreening
AT gobecstanislav towardsdiscoveryofinhibitorsoftheundecaprenylpyrophosphatephosphatasebacabyvirtualhighthroughputscreening
AT touzethierry towardsdiscoveryofinhibitorsoftheundecaprenylpyrophosphatephosphatasebacabyvirtualhighthroughputscreening