Virtual Screening Approach and Investigation of Structure-Activity Relationships To Discover Novel Bacterial Topoisomerase Inhibitors Targeting Gram-Positive and Gram-Negative Pathogens.
Gabriele MagaròFederica PratiBarbara GarofaloGaia CorsoGuido FurlottiClaudia ApicellaGiorgina ManganoNoemi D'AtanasioDaniel RobinsonFrancesco Paolo Di GiorgioRosella OmbratoPublished in: Journal of medicinal chemistry (2019)
Bacterial resistance is increasing rapidly, requiring urgent identification of new antibacterial drugs that are effective against multidrug-resistant pathogens. Novel bacterial topoisomerase inhibitors (NBTIs) provide a new strategy for investigating the well-validated DNA gyrase and topoisomerase IV targets while preventing cross-resistance issues. On this basis, starting from a virtual screening campaign and subsequent structure-based hit optimization guided by X-ray studies, a novel class of piperazine-like NBTIs with outstanding enzymatic activity against Staphylococcus aureus and Escherichia coli DNA gyrase and topoisomerase IV was identified. Notably, compounds (±)-33, (±)-35, and (±)-36 with potent and balanced multitarget enzymatic profiles exhibited excellent efficacy against selected Gram-positive and Gram-negative pathogens, as well as clinically relevant resistant strains. Overall, the new NBTI chemotype described herein, owing to the broad-spectrum antibacterial activity and favorable in vitro safety profile, might serve as a basis for the development of novel treatments against serious infections.
Keyphrases
- gram negative
- multidrug resistant
- escherichia coli
- drug resistant
- klebsiella pneumoniae
- acinetobacter baumannii
- staphylococcus aureus
- circulating tumor
- hydrogen peroxide
- single molecule
- cell free
- silver nanoparticles
- high resolution
- nitric oxide
- anti inflammatory
- cancer therapy
- mass spectrometry
- drug delivery
- magnetic resonance
- magnetic resonance imaging
- cystic fibrosis
- dna binding