Experimental and Molecular Docking Studies of Cyclic Diphenyl Phosphonates as DNA Gyrase Inhibitors for Fluoroquinolone-Resistant Pathogens. | LitMetric
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 (- and -) as DNA gyrase inhibitors. The synthesized compounds were screened for their activity (antibacterial and DNA gyrase inhibition) against ciprofloxacin-resistant and clinical isolates having mutations (deletion and substitution) in QRDR region of DNA gyrase. The target compound () that exhibited the most potent activity against ciprofloxacin Gram-negative clinical isolates was selected to screen its inhibitory activity against DNA gyrase displayed IC of 12.03 µM. In addition, a docking study was performed with inhibitor (), 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 () to DNA gyrase is mediated and modulated by divalent Mg 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.
Developing and creating novel antibiotics is one of the most important targets in treating infectious diseases. Novel coumarins were synthesized and characterized using different spectroscopic techniques such as Fourier Transform Infrared (FTIR), Nuclear magnetic resonanceH and C and mass spectroscopy (MS). All of the synthesized compounds have been tested for activity and sensitivity against the microbial strains of B.
DNA supercoiling in biological systems can occur via three mechanisms. The first is by the activity of DNA topoisomerases, such as DNA gyrases, that can increase or reduce the linking number of relaxed DNA (Lk). The second is via DNA translocation motors, such as RNA and DNA polymerases, that produce twin supercoiled DNA domains: one positively supercoiled in front and one negatively supercoiled behind.
New techniques in biomolecular dynamics allow manipulation of forces at the single-molecule level, helping to advance our understanding.
A newly developed method significantly increases the throughput of force spectroscopy, enabling analysis of thousands of molecules simultaneously, including rare enzymatic events.
The chapter includes experimental procedures for studying DNA gyrase's supercoiling dynamics and introduces a software platform to classify dynamic behaviors, making it applicable to various complex enzymatic processes.
Mycobacterium tuberculosis is a human pathogen that causes Tuberculosis (TB) disease. Researchers have reported the activity of traditional medicinal plants against human pathogens. However, antimycobacterial studies of medicinal plants against M.
In this Letter, we present a small series of novel bacterial topoisomerase inhibitors (NTBIs) that exhibit both potent inhibition of DNA gyrase and potent antimycobacterial activity. The disclosed crystal structure of DNA gyrase in complex with DNA and compound from this NBTI series reveals the binding mode of an NBTI in the GyrA binding pocket and confirms the presence and importance of halogen bonding for the excellent on-target potency. In addition, we have shown that compound is a promising DNA gyrase inhibitor, with an IC for gyrase of 0.
