Activity of Thiourea-Linked Diamidines against Multidrug-Resistant Staphylococcus aureus

Abstract

Staphylococcus aureus is a leading cause of antibiotic-resistant infections worldwide. Therefore, there is a constant need to develop new growth inhibitors. Pentamidine analogs (PAs) composed of thiourea-linked amidines were evaluated for activity against methicillin-resistant S. aureus (MRSA) and other Gram-positive bacteria. S. aureus, MRSA, Staphylococcus epidermidis, Streptococcus pyogenes, Mycobacterium, and Bacillus were highly susceptible with minimal inhibitory concentration (MIC) values ranging from 1.56 to 6.25 μM, whereas Enterococcus species and Clostridioides difficile were not as susceptible with MICs of 50 to ≥100 μM. For S. aureus, MRSA and VISA strains, PAs showed ∼4-fold lower MICs when compared to pentamidine (PNT). The concentration of PAs needed to lyse 50% of red blood cells (HC50) was ∼16–32-fold higher than their corresponding MICs. For PNT, a lower HC50/MIC range of 1.25–5 was observed. Approximately 60% of MRSA was cleared from infected Caenorhabditis elegans by the PAs. PAs also provided 100% protection in a septicemia model of infected mice. Morphological changes induced by these compounds indicate disruption of cell membrane integrity, where >80% of treated bacterial cells took up propidium iodide in a permeation assay. Importantly, there was a lack of resistance observed with the PAs, compared to the fairly rapid and stable resistance occurrence for drugs commonly used to treat S. aureus infection. These results reflect the potential of such compounds as potential new tools to optimize and combat the menace of drug-resistant S. aureus.