Development of Novel Bacterial Topoisomerase Inhibitors Assisted by Computational Screening.
Joshua W PowellChelsea A MannPaul D TothSheri NolanAnja SteinertClarissa OveJustin T SeffernickDaniel J WozniakRazieh KebriaeiSteffen LindertNeil OsheroffJack C YalowichMark J Mitton-FryPublished in: ACS medicinal chemistry letters (2024)
Multidrug-resistant bacterial infections pose an ever-evolving threat to public health. Since the outset of the antibacterial age, bacteria have developed a multitude of diverse resistance mechanisms that suppress the effectiveness of current therapies. New drug entities, such as Novel Bacterial Topoisomerase Inhibitors (NBTIs), can circumvent this major issue. A computational docking model was employed to predict the binding to DNA gyrase of atypical NBTIs with novel pharmacophores. Synthesis of NBTIs based on computational docking and subsequent antibacterial evaluation against both Gram-positive and Gram-negative bacteria yielded congeners with outstanding anti-staphylococcal activity and varying activity against select Gram-negative pathogens.
Keyphrases
- gram negative
- multidrug resistant
- public health
- drug resistant
- acinetobacter baumannii
- molecular dynamics
- klebsiella pneumoniae
- molecular dynamics simulations
- randomized controlled trial
- systematic review
- protein protein
- staphylococcus aureus
- silver nanoparticles
- emergency department
- circulating tumor
- drug induced
- pseudomonas aeruginosa
- antimicrobial resistance
- wound healing