Discovery and structure-activity relationships of the quinolinequinones: Promising antimicrobial agents and mode of action evaluation.

Abstract

In our pursuit of developing the novel, potent, and selective antimicrobial agents, we managed to obtain the quinolinequinone for their antimicrobial profile with minimal inhibitory concentrations (MICs) determined against a panel of seven bacterial strains (three gram-positive and four gram-negative bacteria) and three fungi. The structure-activity relationship (SAR) for the quinolinequinone class of antimicrobials was determined. Interestingly, QQ1, QQ4, QQ6-9, QQ12, and QQ13 displayed equal antibacterial potential against S. aureus (MIC=1.22 mg/L), respectively, to the standard positive control Cefuroxime-Na. QQ10 had the best inhibitory activity with the MIC value of 1.22 mg/L (fourfold more potent compared to reference standard Clotrimazole) against Candida albicans. On the other hand, while QQ10 is not too effective against gram-positive bacteria as much as the other analogs, QQ10 was the most effective quinolinequinones against fungi. Selected quinolinequinones were further evaluated for the mode of action, using in vitro antibiofilm activity, bactericidal activity by using time-kill curve assay, antibiofilm activity, and potential antimicrobial activity against each of 32 clinically obtained resistant strains of Gram-positive Bacteria. The results also revealed that the QQ14 had specific antifungal activity against fungi in particular C. albicans. Our results clearly showed that quinolinequinones are much more active in the inhibition of the biofilm attachment process than the inhibition of mature biofilm formation. Thus, as treatment options are narrowing for Methicillin-resistant Staphylococcus spp., Vancomycin-resistant Staphylococcus spp. daily, the quinolinequinones reported herein display promise as the lead candidates for further clinical applications against serious infections.