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Activity of Thiourea-Linked Diamidines against Multidrug-Resistant Staphylococcus aureus
Yi Jin1, Sandra Story2, Jordan Chamberlin1,2
1Laboratory of Medicinal Chemistry, Department of Chemistry, Clemson University, Clemson, South Carolina29634, United States.
ACS Infectious Diseases
|August 14, 2026
Summary
New pentamidine analogs (PAs) show potent activity against antibiotic-resistant bacteria like MRSA. These compounds effectively combat infections in animal models with low toxicity and no observed resistance, offering a promising alternative to current treatments.
Area of Science:
- Microbiology
- Medicinal Chemistry
- Infectious Diseases
Background:
- Staphylococcus aureus is a major cause of global antibiotic-resistant infections.
- Development of novel antimicrobial agents is crucial to combat resistant strains.
- Pentamidine analogs (PAs) offer a potential new class of antibacterial compounds.
Purpose of the Study:
- To evaluate the antibacterial activity of pentamidine analogs (PAs) against Gram-positive bacteria, including methicillin-resistant S. aureus (MRSA).
- To assess the in vivo efficacy and safety profile of PAs.
- To investigate the mechanism of action and resistance potential of PAs.
Main Methods:
- Minimal inhibitory concentration (MIC) assays were performed against various bacterial strains.
- Cytotoxicity was assessed using red blood cell lysis assays (HC50).
- In vivo efficacy was evaluated in Caenorhabditis elegans and mouse septicemia models.
- Bacterial cell membrane integrity was assessed using propidium iodide uptake assays.
Main Results:
- PAs exhibited potent activity against S. aureus, MRSA, and other Gram-positive bacteria with low MIC values (1.56–6.25 μM).
- PAs demonstrated significantly lower MICs (approx. 4-fold) compared to pentamidine against S. aureus, MRSA, and VISA strains.
- PAs showed a favorable safety profile with high HC50/MIC ratios (16–32-fold), indicating low toxicity.
- In vivo studies showed significant bacterial clearance in C. elegans (60% MRSA clearance) and complete protection in mouse septicemia models.
- Mechanism of action involves disruption of bacterial cell membrane integrity, with >80% propidium iodide uptake observed.
- No resistance was observed with PAs, contrasting with rapid resistance development for conventional drugs.
Conclusions:
- Pentamidine analogs are highly effective against drug-resistant Gram-positive bacteria, including MRSA.
- PAs demonstrate promising in vivo efficacy and a favorable safety profile.
- The lack of observed resistance suggests PAs could be valuable in combating antibiotic resistance.
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