Discovery and s tructure–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 structureactivity 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.

Exploring the Relationships between Structure and Antimicrobial Potency of Quinolinequinones

“…To develop improved antimicrobial molecules, we adopted a pharmacophore approach to merge the quinolinequinone and aryl amines containing an ester moiety. The present work extends our ongoing efforts toward developing biologically active molecules with high efficiency [ 26 , 27 ].…”

“…Regarding the development of effective antimicrobial agents, particularly against methicillin-resistant Staphylococcus spp. strains, quinolinequinones are classified as having the potential for developing novel antibacterial candidates [ 27 , 30 , 31 ]. Other noteworthy examples are sulfanyl and amino analogs of quinolinequinones, which play a significant role against MRSA, as published by Yildirim and Bayrak [ 32 , 33 ].…”

“…Biofilm attachment and inhibition of biofilm formation assays were performed as per the previously described method with some modifications [ 26 ]. According to the previously reported method by Yıldız et al and Mataracı Kara et al [ 27 ] for biofilm attachment assays, an overnight culture of S. epidermidis ATCC 35984 and S. aureus ATCC 43300 were added to each well of a 96-well tissue culture microtiter plate (Greiner, catalog number: M0812) with 1/10 the MICs of QQ2 and QQ6 compounds, respectively. The plates were incubated for 1, 2, and 4 h for the studied isolates at 37 °C [ 26 , 27 ].…”

“…We also determined the inhibition of biofilm formation methods by using those previously reported by Yıldız et al and Mataracı-Kara et al [ 26 , 27 ]. According to their experiments [ 26 , 27 ] for inhibition of biofilm formation, TSB-glucose (BD Difco, catalog number: DF0370-17-3) for S. epidermidis and S. aureus were incubated at 37 °C, 24 h, with the tested QQ compounds at 1 × MIC, 1/10 the MIC, and 1/100 the MIC in 96-well tissue culture, respectively. Six wells were used for each molecule.…”

Active Quinolinequinones against Methicillin‐Resistant Staphylococcus spp

“…[25][26][27] Quinolinequinones and their related compounds have a wide range of pharmaceutical applications due to their antibacterial, antifungal, and anticancer properties. [19,28,29] Based on the standard Staphylococcus spp. 's MIC results, we also aimed to determine the potential antibacterial activities of selected active molecules QQ3 and QQ5 against 32 clinically obtained resistant strains of Staphylococcus spp.…”