Abstract
Bacterial resistance to antibiotics remains an imposing global public health challenge. Of the most serious pathogens, methicillin-resistant Staphylococcus aureus (MRSA) is problematic given strains have emerged that exhibit resistance to several antibiotic classes including β-lactams and agents of last resort such as vancomycin. New antibacterial agents composed of unique chemical scaffolds are needed to counter this public health challenge. The present study examines two synthetic diphenylurea compounds 1 and 2 that inhibit growth of clinically-relevant isolates of MRSA at concentrations as low as 4 µg/mL and are non-toxic to human colorectal cells at concentrations up to 128 μg/mL. Both compounds exhibit rapid bactericidal activity, completely eliminating a high inoculum of MRSA within four hours. MRSA mutants exhibiting resistance to 1 and 2 could not be isolated, indicating a low likelihood of rapid resistance emerging to these compounds. Bacterial cytological profiling revealed the diphenylureas exert their antibacterial activity by targeting bacterial cell wall synthesis. Both compounds demonstrate the ability to resensitize vancomycin-resistant Staphylococcus aureus to the effect of vancomycin. The present study lays the foundation for further investigation and development of diphenylurea compounds as a new class of antibacterial agents.
Highlights
Antibiotics have been critical therapeutic allies for healthcare-providers to treat bacterial infections for over 80 years
Diphenylurea compounds 1 and 2 retained their antibacterial activity against strains of S. aureus exhibiting high-level resistance to the antibiotics mupirocin (NRS107) and vancomycin (VRS4, VRS7, VRS10 and VRS11a)
1 and 2 exhibited potent activity against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) that are resistant to multiple classes of antibiotics including ansamycins (NRS107), β-lactams, macrolides (NRS384 and NRS483), tetracyclines (NRS384), and fluoroquinolones (NRS387), indicating cross-resistance between these antibiotic classes and the diphenylurea compounds is unlikely to occur
Summary
Antibiotics have been critical therapeutic allies for healthcare-providers to treat bacterial infections for over 80 years. The increasing prevalence of clinical isolates of bacteria exhibiting resistance to one or more classes of antibiotics poses a significant global public health. Diphenylurea compounds as a new antibiotic class. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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