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Targeting Biofilm Associated Staphylococcus aureus Using Resazurin Based Drug-susceptibility Assay
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Targeting Biofilm Associated Staphylococcus aureus Using Resazurin Based Drug-susceptibility Assay

Published on: May 5, 2016

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
PubMed

Insights

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.
Keywords:
Gram-positive bacteriadiamidinesdrug effluxmultidrug-resistant Staphylococcus aureuspentamidine

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