2. Academic Validation
  3. Exploring the structure-activity relationships of diphenylurea as an antibacterial scaffold active against methicillin- and vancomycin-resistant Staphylococcus aureus

Exploring the structure-activity relationships of diphenylurea as an antibacterial scaffold active against methicillin- and vancomycin-resistant Staphylococcus aureus

  • Eur J Med Chem. 2022 Apr 15;234:114204. doi: 10.1016/j.ejmech.2022.114204.
Mohamed M Elsebaie 1,  Hanzada T Nour El-Din 2,  Nader S Abutaleb 3,  Abdelrahman A Abuelkhir 1,  Hsin-Wen Liang 4,  Ahmed S Attia 5,  Mohamed N Seleem 6,  Abdelrahman S Mayhoub 7
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University, Cairo, 11884, Egypt.
  • 2 Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt.
  • 3 Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24061, USA; Department of Microbiology and Immunology, Zagazig University, Zagazig, 44519, Egypt.
  • 4 Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24061, USA.
  • 5 Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt; Department of Microbiology and Immunology, School of Pharmacy, Newgiza University, Giza, Egypt.
  • 6 Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24061, USA; Center for Emerging, Zoonotic and Arthropod-borne Pathogens, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24061, USA. Electronic address: seleem@vt.edu.
  • 7 Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University, Cairo, 11884, Egypt; Nanoscience Program, University of Science and Technology, Zewail City of Science and Technology, Giza, Egypt. Electronic address: amayhoub@zewailcity.edu.eg.
PMID: 35279608 DOI: 10.1016/j.ejmech.2022.114204
Abstract

A set of structurally related diphenylurea derivatives bearing aminoguanidine moiety were synthesized, and their Antibacterial activity was assessed against a panel of multi-drug resistant Gram-positive clinical isolates. Two compounds 6 and 24 were identified with better bacteriological profile than the lead compound I. The multi-step resistance development studies indicated that MRSA are less likely to develop resistance toward diphenylurea compounds. Moreover, these compounds demonstrated a prolonged post-antibiotic effect than that of vancomycin. Furthermore, compounds 6 and 24 were able to re-sensitize VRSA to vancomycin, resulting in 8- to more than 32-fold improvement in vancomycin MIC values against clinical VRSA isolates. Finally, when assessed in an in vivo skin Infection mouse model, the efficacy of compound 24 was very comparable to that of the commercially available fusidic acid ointment. Additionally, the diphenylurea 24 did not have a pronounced effect on the animal weights along the experiment indicating its safety and tolerability to mice. Taken together, these results indicate that the diphenylurea scaffold merits further investigation as a promising anti-staphylococcal treatment option.

Keywords

Antimicrobial resistance; MRSA skin Infection animal model; Methicillin-resistant Staphylococcus aureus; Post-antibiotic effect.

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