Discovery of thiazolylcyanovinyl benzopyridone acids: Potential new generation antibacterial oxacins?

Abstract

Here we reported a unique class of new structural thiazolylcyanovinyl benzopyridone acids (TBAs) with large potential to defeat the intractable global bacterial resistance. Some prepared TBAs demonstrated broad-spectrum antibacterial ability, especially ethyl TBA 7b gave low MIC values of 0.25–0.5 μg/mL against all the tested bacteria, superior to norfloxacin and clinafloxacin. The highly active molecule 7b not only showed imperceptible hemolysis, cytotoxicity, toxicity in vivo and drug resistance, but also effectually eradicated mature biofilm and rapidly sterilized Klebsiella pneumonia. Moreover, TBA 7b exhibited high therapeutic efficacy in mouse model of wound infection. Mechanism explorations implied that TBA 7b could intercalate into DNA and act on gyrase-DNA complex to block DNA supercoiling, trigger oxidative stress and inhibit lactate dehydrogenase to reduce metabolism, resulting in bacterial death and intracellular protein leakage. These results suggested that thiazolylcyanovinyl benzopyridone acids should hold the large promise for being exploited as next-generation antibacterial oxcains.