Klug, Dana M;
Tse, Edwin G;
Silva, Daniel G;
Cao, Yafeng;
Charman, Susan A;
Chauhan, Jyoti;
Crighton, Elly;
... Todd, Matthew H; + view all
(2023)
Open Source Antibiotics: Simple Diarylimidazoles Are Potent against Methicillin-Resistant Staphylococcus aureus.
ACS Infectious Diseases
10.1021/acsinfecdis.3c00286.
(In press).
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Abstract
Antimicrobial resistance (AMR) is widely acknowledged as one of the most serious public health threats facing the world, yet the private sector finds it challenging to generate much-needed medicines. As an alternative discovery approach, a small array of diarylimidazoles was screened against the ESKAPE pathogens, and the results were made publicly available through the Open Source Antibiotics (OSA) consortium (https://github.com/opensourceantibiotics). Of the 18 compounds tested (at 32 μg/mL), 15 showed >90% growth inhibition activity against methicillin-resistant Staphylococcus aureus (MRSA) alone. In the subsequent hit-to-lead optimization of this chemotype, 147 new heterocyclic compounds containing the diarylimidazole and other core motifs were synthesized and tested against MRSA, and their structure-activity relationships were identified. While potent, these compounds have moderate to high intrinsic clearance and some associated toxicity. The best overall balance of parameters was found with OSA_975, a compound with good potency, good solubility, and reduced intrinsic clearance in rat hepatocytes. We have progressed toward the knowledge of the molecular target of these phenotypically active compounds, with proteomic techniques suggesting TGFBR1 is potentially involved in the mechanism of action. Further development of these compounds toward antimicrobial medicines is available to anyone under the licensing terms of the project.
| Type: | Article |
|---|---|
| Title: | Open Source Antibiotics: Simple Diarylimidazoles Are Potent against Methicillin-Resistant Staphylococcus aureus |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1021/acsinfecdis.3c00286 |
| Publisher version: | https://doi.org/10.1021/acsinfecdis.3c00286 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third-party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | Drug discovery, antibacterials, antibiotics, bioactive molecules, open science, organic synthesis |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10182369 |
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