Abstract
DNA gyrase and topoisomerase IV are proven to be validated targets in the design of novel antibacterial drugs. In this study, we report the antibacterial evaluation and molecular docking studies of previously synthesized two series of cyclic diphenylphosphonates (1a–e and 2a–e) as DNA gyrase inhibitors. The synthesized compounds were screened for their activity (antibacterial and DNA gyrase inhibition) against ciprofloxacin-resistant E.coli and Klebsiella pneumoniae clinical isolates having mutations (deletion and substitution) in QRDR region of DNA gyrase. The target compound (2a) that exhibited the most potent activity against ciprofloxacin Gram-negative clinical isolates was selected to screen its inhibitory activity against DNA gyrase displayed IC50 of 12.03 µM. In addition, a docking study was performed with inhibitor (2a), to illustrate its binding mode in the active site of DNA gyrase and the results were compatible with the observed inhibitory potency. Furthermore, the docking study revealed that the binding of inhibitor (2a) to DNA gyrase is mediated and modulated by divalent Mg2+ at good binding energy (–9.08 Kcal/mol). Moreover, structure-activity relationships (SARs) demonstrated that the combination of hydrazinyl moiety in conjunction with the cyclic diphenylphosphonate based scaffold resulted in an optimized molecule that inhibited the bacterial DNA gyrase by its detectable effect in vitro on gyrase-catalyzed DNA supercoiling activity.
Highlights
Infections are among the major causes of human morbidity and mortality
We tested the effect of the inhibitor by showing the difference in the mobility between relaxed and supercoiled DNA. the result showed that the compound (2a) has potency in comparison with ciprofloxacin against the enzyme activity explored by inhibiting the DNA gyrase enzyme at different concentrations, where relaxed DNA substrate become completely negatively supercoiled at a lower concentration, and with increasing concentration to 50 μM inhibit supercoiling completely that is noticed with the addition of ciprofloxacin at 25μM that showed by DNA supercoiling (Figure 6)
The effect of synthesized compound (2a) as a quinolone inhibitor compared with ciprofloxacin at different concentrations was determined using E. coli Gyrase Microplate Assay Kit (Inspiralis, Norwich, UK) based on the DNA Supercoiling using DNA gyrase enzyme according to manufacturer’s instructions [52]
Summary
Infections are among the major causes of human morbidity and mortality. The pharmaceutical industry is unable to keep up with the growing need for effective novel antibacterial drugs [1]; The main reason for this situation is the rapid bacterial adaptation to antibiotics; which, results in resistance development after antibacterial drugs are introduced into clinical use. According to the screening results of the antibacterial activity, compound (2a) was selected to use as a gyrase enzyme inhibitor of E. coli DNA gyrase, the compound markedly inhibited both ciprofloxacin-resistant mutant and the wild-type strain with different behavior toward Gram-positive bacteria that was less susceptible in comparison with Gramnegative bacteria. This inhibition was performed through this mechanism depending on genetic approaches to probe the nature of the mechanism action. We tested the effect of the inhibitor by showing the difference in the mobility between relaxed and supercoiled DNA. the result showed that the compound (2a) has potency in comparison with ciprofloxacin against the enzyme activity explored by inhibiting the DNA gyrase enzyme at different concentrations, where relaxed DNA substrate become completely negatively supercoiled at a lower concentration, and with increasing concentration to 50 μM inhibit supercoiling completely that is noticed with the addition of ciprofloxacin at 25μM that showed by DNA supercoiling (Figure 6)
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