In silico study and biological screening of benzoquinazolines as potential antimicrobial agents against methicillin-resistant Staphylococcus aureus, carbapenem-resistant Klebsiella pneumoniae, and fluconazole-resistant Candida albicans. (November 2021)

• Record Type: Journal Article
• Authors: Abuelizz, Hatem A.; Marzouk, Mohamed; Bakhiet, Ahmed; Abdel-Aziz, Marwa M.; Ezzeldin, Essam; Rashid, Harunor; Al-Salahi, Rashad
• Is Part Of: Microbial pathogenesis. Volume 160(2021)
• Publication Date: 2021-11
• Subjects: Klebsiella pneumoniae -- Benzoquinazolines -- Staphylococcus aureus -- Candida albicans -- Docking study; Pathogenic microorganisms -- Periodicals; Pathology, Molecular -- Periodicals; Communicable Diseases -- microbiology -- Periodicals; Communicable Diseases -- parasitology -- Periodicals; Micro-organismes pathogènes -- Périodiques; Pathologie moléculaire -- Périodiques; Electronic journals; 616.9041
• DOI: 10.1016/j.micpath.2021.105157
• Languages: English
• ISSNs: 0882-4010

Abstract

Abstract: Globally, antibiotic-resistant pathogens have become a serious threat to public health. The use of drugs having structures different from those applied in the clinical treatments of bacterial infections is a well-known potential solution to the antibiotic resistance crisis. Benzo-[ g ]-quinazolines were identified by our research group as a new class of antimicrobial agents. Herein, to follow-up the research on such compounds, three benzo-[ g ]-quinazolines (1–3 ) were studied, as in vitro antibacterial candidates against methicillin-resistant Staphylococcus aureus (MRSA), carbapenem-resistant Klebsiella pneumoniae, and fluconazole-resistant Candida albicans, as well. The minimum inhibitory concentration (MIC) assay for benzoquinazolines was carried out via the calorimetric broth microdilution method using the XTT assay in comparison with vancomycin, ciprofloxacin, and ketoconazole as reference drugs. The target compounds 1–3 revealed high variation in their activity against the examined resistant microbial strains. Benzoquinazoline 3 exhibited a more potent effect against the resistant strains compared with the reference drugs. A docking study was performed to identify the interactions between the benzoquinazolines 1–3 and ligand proteins (OXA-48 carbapenemase, β-lactamase, and sterol 14-alpha demethylase (CYP51)) at the active sites. Benzoquinazolines 1–3 showed very weak cytotoxicity against human lung fibroblast normal cells (WI-38). The targets showed promising antimicrobial effects against the three resistant strains. These findings may inform future inhibitor discoveries targeting penicillin-binding proteins. Highlights: Benzo-[ g ]-quinazolines were identified by our research group as a new class of antimicrobial agents. Benzo-[ g ]-quinazolines(1-3 ) were investigated in vitro against methicillin-resistant staphylococcus aureus ( MRSA), carbapenem-resistant klebsiella pneumoniae, and fluconazole-resistant candida albicans, as well. The target compounds 1-3 revealed high variation in their activity against the examined resistant microbial strains. Compound 3 showed the highest activity against three examined strains, giving MIC50 values of 0.67, 0.32 and 0.53 µg/mL in relation to the reference drugs. The target benzoquinazolines demonstrated very weak cytotoxicity against human lung fibroblast normal cells (WI-38) with CC50 of 390.1±0.94, 145.9±2.1 and 243.6±1.3 for compounds 3, 2 and 1, respectively.