Experimental and Molecular Docking Studies of Cyclic Diphenyl Phosphonates as DNA Gyrase Inhibitors for Fluoroquinolone-Resistant Pathogens

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.

Synthesis, Characterization, and Docking Study of Novel Thioureidophosphonate-Incorporated Silver Nanocomposites as Potent Antibacterial Agents

“…Therefore, α-APs were deemed a worthy choice for AgNPs dispersion to bring extra synergistic antibacterial properties as part of a sustainable approach. Remarkably, our group has long been involved in developing different series of phosphonate derivatives in medical applications as antibacterial agents [ 45 , 46 ], urokinase-type plasminogen inhibitors [ 47 ], DNA gyrase inhibitors [ 48 ], anticancer [ 49 ], antifungal agents [ 49 ]. This is in addition to designing and synthesizing other potent antibacterial agents for various industrial applications [ 22 , 50 , 51 ].…”

Identification of Potential DNA Gyrase Inhibitors: Virtual Screening, Extra-Precision Docking and Molecular Dynamics Simulation Study

“…Alfonso et al ., have discovered a few novels and structurally diverse DNA gyrase inhibitors through a fluorescence-based high-throughput screening assay (Alfonso et al, 2022). Saleh et al ., have employed experimental and computational (molecular docking) studies to discover some cyclic diphenyl phosphonates as DNA gyrase inhibitors for fluoroquinolone-resistant pathogens (Saleh et al, 2022).…”

New Biomolecules and Drug Delivery Systems as Alternatives to Conventional Antibiotics

“…Discovering new pharmaceutical strategies to fight infection is a very challenging and time-consuming process. Considering DNA gyrase and topoisomerase IV are known targets for novel antibacterial drug design, Saleh et al demonstrated the effectiveness of diphenylphosphonates as DNA gyrase inhibitors, with great potentially for new pharmaceutical formulations [7]. Furthermore, Baranova et al followed a different route and resorted to live biosensors for ultra-high-throughput screening for deep profiling of antibacterial activity and antibiotic discovery [8].…”