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Identification of a novel DNA repair inhibitor using an in silico driven approach shows effective combinatorial activity with genotoxic agents against multidrug-resistant Escherichia coli

Bernacchia, Lorenzo, Paris, Antoine, Gupta, Arya, Charman, Robert James, McGreig, Jake E., Wass, Mark N., Kad, Neil M (2024) Identification of a novel DNA repair inhibitor using an in silico driven approach shows effective combinatorial activity with genotoxic agents against multidrug-resistant Escherichia coli. Protein science : a publication of the Protein Society, 33 (4). Article Number e4948. ISSN 1469-896X. E-ISSN 1469-896X. (doi:10.1002/pro.4948) (KAR id:105464)

Abstract

Increasing antimicrobial drug resistance represents a global existential threat. Infection is a particular problem in immunocompromised individuals, such as patients undergoing cancer chemotherapy, due to the targeting of rapidly dividing cells by antineoplastic agents. We recently developed a strategy that targets bacterial nucleotide excision DNA repair (NER) to identify compounds that act as antimicrobial sensitizers specific for patients undergoing cancer chemotherapy. Building on this, we performed a virtual drug screening of a ~120,000 compound library against the key NER protein UvrA. From this, numerous target compounds were identified and of those a candidate compound, Bemcentinib (R428), showed a strong affinity toward UvrA. This NER protein possesses four ATPase sites in its dimeric state, and we found that Bemcentinib could inhibit UvrA's ATPase activity by ~90% and also impair its ability to bind DNA. As a result, Bemcentinib strongly diminishes NER's ability to repair DNA in vitro. To provide a measure of in vivo activity we discovered that the growth of Escherichia coli MG1655 was significantly inhibited when Bemcentinib was combined with the DNA damaging agent 4-NQO, which is analogous to UV. Using the clinically relevant DNA-damaging antineoplastic cisplatin in combination with Bemcentinib against the urological sepsis-causing E. coli strain EC958 caused complete growth inhibition. This study offers a novel approach for the potential development of new compounds for use as adjuvants in antineoplastic therapy.

Item Type: Article
DOI/Identification number: 10.1002/pro.4948
Additional information: For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.
Uncontrolled keywords: antimicrobial; antibiotic resistance; cancer chemotherapy; cooperativity; inhibitor; microbial infection; nucleotide excision repair; protein inhibition; virtual screen
Subjects: Q Science
Divisions: Divisions > Division of Natural Sciences > Biosciences
Funders: Cancer Research UK (https://ror.org/054225q67)
Biotechnology and Biological Sciences Research Council (https://ror.org/00cwqg982)
SWORD Depositor: JISC Publications Router
Depositing User: JISC Publications Router
Date Deposited: 08 Apr 2024 14:04 UTC
Last Modified: 05 Nov 2024 13:11 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/105464 (The current URI for this page, for reference purposes)

University of Kent Author Information

Bernacchia, Lorenzo.

Creator's ORCID:
CReDIT Contributor Roles:

Paris, Antoine.

Creator's ORCID:
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Charman, Robert James.

Creator's ORCID:
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McGreig, Jake E..

Creator's ORCID: https://orcid.org/0000-0002-3068-5624
CReDIT Contributor Roles:

Wass, Mark N..

Creator's ORCID: https://orcid.org/0000-0001-5428-6479
CReDIT Contributor Roles:

Kad, Neil M.

Creator's ORCID: https://orcid.org/0000-0002-3491-8595
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