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

Autor: Jukič M; University of Maribor, Faculty of Chemistry and Chemical Engineering, Laboratory of Physical Chemistry and Chemical Thermodynamics, Smetanova 17, Maribor SI-2000, Slovenia.; University of Primorska, Faculty of Mathematics, Natural Sciences and Information Technologies, Glagoljaška 8, Koper SI-6000, Slovenia., Auger R; Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Gif-sur-Yvette FR-91198, France., Folcher V; Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Gif-sur-Yvette FR-91198, France., Proj M; Univerza v Ljubljani, Fakulteta za Farmacijo, Aškerčeva cesta 7, Ljubljana SI-1000, Slovenia., Barreteau H; Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Gif-sur-Yvette FR-91198, France., Gobec S; Univerza v Ljubljani, Fakulteta za Farmacijo, Aškerčeva cesta 7, Ljubljana SI-1000, Slovenia., Touzé T; Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Gif-sur-Yvette FR-91198, France.
Jazyk: angličtina
Zdroj: Computational and structural biotechnology journal [Comput Struct Biotechnol J] 2022 May 11; Vol. 20, pp. 2360-2371. Date of Electronic Publication: 2022 May 11 (Print Publication: 2022).
DOI: 10.1016/j.csbj.2022.05.010
Abstrakt: 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.
Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(© 2022 The Author(s).)
Databáze: MEDLINE
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