Potentiating the intracellular killing of Staphylococcus aureus by dihydroquinazoline analogues as NorA efflux pump inhibitor. (15th January 2022)

• Record Type: Journal Article
• Authors: Deka, Banani; Suri, Mrinaly; Sarma, Sangita; Devi, Moirangthem Veigyabati; Bora, Anamika; Sen, Tejosmita; Dihingia, Anjum; Pahari, Pallab; Singh, Anil Kumar
• Is Part Of: Bioorganic & medicinal chemistry. Volume 54(2022)
• Publication Date: 2022-01-15
• Subjects: Staphylococcus aureus -- Fluoroquinolone resistance -- NorA efflux pump -- Dihydroquinazoline -- Efflux pump inhibitor -- qRT-PCR -- Intracellular killing; NX Norfloxacin -- EB Ethidium Bromide -- EPI Efflux Pump Inhibitor -- MIC Minimum Inhibitory Concentration -- MF Modulation Factor -- SI Sub Inhibitory Concentration -- FESEM Field Emission Scanning Electron Microscope; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2021.116580
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Dihydroquinazoline analogues as NorA efflux pump inhibitor, synergistically reduced norfloxacin and Etbr MIC of S. aureus 1199b by 16 modulation folds. Effective log reduction (>10 3 log) in bacterial kill kinetics assay in presence of these analogues at 4 h confirmed their bactericidal nature. Dihydroquinazoline analogues, significantly able to down regulate the norA gene expression in the presence of sub-inhibitory concentration of norfloxacin. The most important finding of this study was the ability of analogues to significantly reduce the intracellular S. aureus 1199b (>10 3 log) in human THP-1 monocytes in presence of norfloxacin. Abstract: Staphylococcus aureus is an emerging human pathogen that has become difficult to treat due to its high resistance against wide range of drugs. Emergence of drug resistant isolates has further convoluted the treatment process. Among different resistance mechanisms, efflux pump proteins play a central role and has made itself a direct approach for therapeutic exploration. To demarcate the role of dihydroquinazoline analogues as NorA efflux pump inhibitor in S. aureus 1199B (NorA over producing) strain total seventeen analogues were synthesized and tested for their modulatory effects on norfloxacin and Etbr resistance. Further accumulation assays, bacterial time kill kinetics, cytotoxicity assay were also carried out. The intracellular killing ability of analogues, as EPI was determined using THP-1 monocytes. The binding interaction of analogues with NorA was also predicted. Dihydroquinazoline analogues notably reduced the MIC of norfloxacin and Etbr in S. aureus 1199B. In addition to their very low toxicity, they showed high Etbr and norfloxacin accumulation respectively. Further effective over time log reduction in bacterial kill kinetics in presence of these analogues confirmed their role as NorA efflux pump inhibitor. FESEM analysis clearly depicted their effect on the cell surface morphology owing to its lyses. The most significant finding of this study was the ability of analogues to significantly reduce the intracellular S. aureus 1199B in human THP-1 monocytes in presence of norfloxacin. Our study has shown for the first time the possibility of developing the dihydroquinazoline analogues as NorA efflux pump inhibitors for S. aureus and control its infection.