Abstract
Drug-resistant Escherichia coli (E. coli) has overburdened the healthcare facilities in recent years and is getting hard to combat, mandating search for novel therapeutics with a broad antibacterial spectrum and high chemotherapeutic index. The 24 kDa domain of DNA gyrase B that is involved in the ATPase activity has been reported to be a promising target for inhibitors. A PDB structure (1KZN) of the 24kD domain of gyrase B with the co-crystallized ligand clorobiocin was used for the docking studies to explore a library of 2924 FDA approved drugs from www.zinc.docking.org. FlexX docking module from Biosolve IT was used for receptor preparation and in silico docking experiments. Docking studies on the pocket created around the reference ligand clorobiocin revealed the best score with diminazene aceturate and it also demonstrated interactions with the crucial amino acids present within the pocket. Diminazene aceturate has been conventionally been used as an antiparasitic molecule in animals and it has also been demonstrated to exhibit repurposing potential in the treatment of disorders triggered due to overproduction of inflammatory cytokines, pulmonary hypertension, ischemia-induced cardiac pathophysiology, etc. among others. Findings from this study indicate the possibility of repurposing the age-old molecule diminazene aceturate into a DNA gyrase B antagonist to combat not just the drug-resistant E. coli but also other gram-negative ESKAPE pathogens. It may also aid in alleviating the inflammatory response induced in the body of the patients suffering from septicemia caused by a variety of Gram-negative bacterial pathogens.
Highlights
E. coli is a gram negative bacterium, normally a commensal inhabiting the human colon, and has proved to be a great experimental organism of choice for all microbiology as well as gene cloning experiments for long
Among many mechanisms of Multiple Drug Resistance (MDR), the predominant one is the plasmid-mediated synthesis of Extended–Spectrum Beta Lactamases (ESBLs), which breakdown the beta lactam antibiotics, including all the three generations of cephalosporins, penicillins and aztreonam witnessed in E. coli and other Gram–ve EKAPE pathogens Enterococcus faecium, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species [6,7]
This kind of approach would make it possible to target DNA gyrase of the drug resistant, pathogenic E. coli, that has become resistant to older antibiotics targeting their cell wall, nucleic acid or protein synthesis etc
Summary
E. coli is a gram negative bacterium, normally a commensal inhabiting the human colon, and has proved to be a great experimental organism of choice for all microbiology as well as gene cloning experiments for long. For carrying out meaningful and productive research on these lines, it is of paramount importance to explore the specific residues of Gyrase B which play a crucial role in maintaining its functionality and stability, and to know which compounds disturb the same This kind of approach would make it possible to target DNA gyrase of the drug resistant, pathogenic E. coli, that has become resistant to older antibiotics targeting their cell wall, nucleic acid or protein synthesis etc. Termed “Drug Repurposing”, this strategy is proving to be very productive, quicker, and more practical towards fighting the menace of multiple drug resistant pathogenic bacteria in general [39] This in silico study was undertaken to analyse the interactions of the GyrB subunit towards a number of inhibitors, in an attempt to find a potential lead against MDR E. coli
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