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Biosensor for Detection of Antibiotic Resistant Staphylococcus Bacteria
Published on: May 8, 2013
Open Source Antibiotics: Simple Diarylimidazoles Are Potent against Methicillin-Resistant Staphylococcus aureus
Dana M Klug1, Edwin G Tse1, Daniel G Silva1,2
1School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, United Kingdom.
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.
Insights
Researchers screened diarylimidazoles against the ESKAPE pathogens, identifying potent compounds against methicillin-resistant Staphylococcus aureus (MRSA). Further optimization led to OSA_975, a promising candidate for developing new antimicrobial medicines.
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Microbiology
Background:
- Antimicrobial resistance (AMR) poses a significant global health threat.
- Private sector investment in novel antibiotic development is limited.
- Open science initiatives are crucial for addressing the AMR crisis.
Purpose of the Study:
- To discover novel antimicrobial compounds through an open-source drug discovery approach.
- To identify and optimize diarylimidazole derivatives with activity against ESKAPE pathogens, particularly MRSA.
- To investigate the structure-activity relationships and potential molecular targets of these compounds.
Main Methods:
- Screening of diarylimidazole compounds against ESKAPE pathogens.
- Hit-to-lead optimization involving synthesis of 147 new heterocyclic compounds.
- Evaluation of antimicrobial activity, intrinsic clearance, and toxicity.
- Proteomic analysis to identify potential molecular targets.
Main Results:
- 15 out of 18 initial compounds showed >90% growth inhibition against MRSA.
- Structure-activity relationships were established for the optimized compound series.
- OSA_975 demonstrated a favorable balance of potency, solubility, and reduced clearance.
- Proteomic data suggests TGFBR1 may be involved in the mechanism of action.
Conclusions:
- Diarylimidazoles represent a viable chemotype for developing new antibiotics against MRSA.
- OSA_975 is a promising lead compound with improved pharmacokinetic properties.
- The open-source approach facilitates collaborative development of urgently needed antimicrobial medicines.
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