Inhibitors of bacterial RNA polymerase transcription complex

Daniel S Wenholz; Michael Miller; Catherine Dawson; Mohan Bhadbhade; David StC Black; Renate Griffith; Hue Dinh; Amy Cain; Peter Lewis; Naresh Kumar

doi:10.1016/j.bioorg.2021.105481

Inhibitors of bacterial RNA polymerase transcription complex

Bioorg Chem. 2022 Jan:118:105481. doi: 10.1016/j.bioorg.2021.105481. Epub 2021 Nov 13.

Authors

Affiliations

¹ School of Chemistry, UNSW Sydney, Kensington, NSW 2502, Australia.
² School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW 2308, Australia.
³ Mark Wainwright Analytical Centre, UNSW Sydney, NSW 2052, Australia.
⁴ Department of Biological Molecular Sciences, Macquarie University, Sydney, NSW 2109, Australia.
⁵ School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW 2308, Australia; School of Chemistry and Molecular Bioscience, University of Wollongong and Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia.
⁶ School of Chemistry, UNSW Sydney, Kensington, NSW 2502, Australia. Electronic address: n.kumar@unsw.edu.au.

PMID: 34801947
DOI: 10.1016/j.bioorg.2021.105481

Abstract

A series of hybrid compounds that incorporated anthranilic acid with activated 1H-indoles through a glyoxylamide linker were designed to target bacterial RNA polymerase holoenzyme formation using computational docking. Synthesis, in vitro transcription inhibition assays, and biological testing of the hybrids identified a range of potent anti-transcription inhibitors with activity against a range of pathogenic bacteria with MICs as low as 3.1 μM. A structure activity relationship study identified the key structural components necessary for inhibition of both bacterial growth and transcription. Correlation of in vitro transcription inhibition activity with in vivo mechanism of action was established using fluorescence microscopy and resistance passaging using Gram-positive bacteria showed no resistance development over 30 days. Furthermore, no toxicity was observed from the compounds in a wax moth larvae model, establishing a platform for the development of a series of new antibacterial drugs with an established mode of action.

Keywords: Antibacterial; DNA Transcription inhibition; Indoles; RNA polymerase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
DNA-Directed RNA Polymerases / antagonists & inhibitors*
DNA-Directed RNA Polymerases / metabolism
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Gram-Positive Bacteria / drug effects*
Gram-Positive Bacteria / enzymology
Microbial Sensitivity Tests
Molecular Structure
Moths
Structure-Activity Relationship

Substances

Anti-Bacterial Agents
Enzyme Inhibitors
DNA-Directed RNA Polymerases