Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold-Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa
Number of Authors: 382023 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 66, no 2, p. 1380-1425Article in journal (Refereed) Published
Abstract [en]
We have developed compounds with a promising activity against Acinetobacter baumannii and Pseudomonas aeruginosa, which are both on the WHO priority list of antibiotic-resistant bacteria. Starting from DNA gyrase inhibitor 1, we identified compound 27, featuring a 10-fold improved aqueous solubility, a 10-fold improved inhibition of topoisomerase IV from A. baumannii and P. aeruginosa, a 10-fold decreased inhibition of human topoisomerase IIα, and no cross-resistance to novobiocin. Cocrystal structures of 1 in complex with Escherichia coli GyrB24 and (S)-27 in complex with A. baumannii GyrB23 and P. aeruginosa GyrB24 revealed their binding to the ATP-binding pocket of the GyrB subunit. In further optimization steps, solubility, plasma free fraction, and other ADME properties of 27 were improved by fine-tuning of lipophilicity. In particular, analogs of 27 with retained anti-Gram-negative activity and improved plasma free fraction were identified. The series was found to be nongenotoxic, nonmutagenic, devoid of mitochondrial toxicity, and possessed no ion channel liabilities.
Place, publisher, year, edition, pages
American Chemical Society , 2023. Vol. 66, no 2, p. 1380-1425
Keywords [en]
antiinfective agent, benzothiazole derivative, DNA topoisomerase (ATP hydrolysing), gyrase inhibitor, Acinetobacter baumannii, chemistry, Escherichia coli, human, metabolism, microbial sensitivity test, Pseudomonas aeruginosa, Anti-Bacterial Agents, Benzothiazoles, DNA Gyrase, Humans, Microbial Sensitivity Tests, Topoisomerase II Inhibitors
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:ri:diva-63982DOI: 10.1021/acs.jmedchem.2c01597Scopus ID: 2-s2.0-85146390921OAI: oai:DiVA.org:ri-63982DiVA, id: diva2:1737399
Note
Funding details: Wellcome Trust, WT, 110072/Z/15/Z, BB/P012523/1; Funding details: Biotechnology and Biological Sciences Research Council, BBSRC, BB/J014524/1; Funding details: Javna Agencija za Raziskovalno Dejavnost RS, ARRS, J1-3030, J1-3031, P1-0208; Funding details: Seventh Framework Programme, FP7, FP7/2007-2013; Funding details: Innovative Medicines Initiative, IMI, 115583; Funding text 1: The research presented in this paper was conducted as part of the ND4BB ENABLE Consortium and has received support from the Innovative Medicines Initiative Joint Undertaking under grant no. 115583, resources of which are comprised of financial contributions from the European Union’s seventh framework program (FP7/2007-2013) and EFPIA companies’ in-kind contribution. The views expressed in this article are the views of the authors, and neither IMI nor the European Union or EFPIA is responsible for any use that may be made of the information contained herein. Financial support from the Slovenian Research Agency (grant nos. P1-0208, J1-3030, J1-3031) was gratefully acknowledged. S.R.H. was supported by an iCASE studentship funded by BBSRC and Redx Pharma Plc (BB/J014524/1). Work in A.M.’s lab was supported by an Investigator Award from the Wellcome Trust (110072/Z/15/Z) and by a BBSRC Institute Strategic Programme Grant (BB/P012523/1). The authors thank Diamond Light Source for access to beamlines I03, I04, I04-1, and I24 under proposals MX18565 and MX25108.
2023-02-162023-02-162023-02-16Bibliographically approved