6m1s
The DNA Gyrase B ATP binding domain of PSEUDOMONAS AERUGINOSA in complex with compound 12o
Structural highlights
FunctionGYRB_PSEAE A type II topoisomerase that negatively supercoils closed circular double-stranded (ds) DNA in an ATP-dependent manner to modulate DNA topology and maintain chromosomes in an underwound state. Negative supercoiling favors strand separation, and DNA replication, transcription, recombination and repair, all of which involve strand separation. Also able to catalyze the interconversion of other topological isomers of dsDNA rings, including catenanes and knotted rings. Type II topoisomerases break and join 2 DNA strands simultaneously in an ATP-dependent manner. Publication Abstract from PubMedThe rise of multidrug resistant (MDR) Gram-negative (GN) pathogens and the decline of available antibiotics that can effectively treat these severe infections are a major threat to modern medicine. Developing novel antibiotics against MDR GN pathogens is particularly difficult as compounds have to permeate the GN double membrane, which has very different physicochemical properties, and have to circumvent a plethora of resistance mechanisms such as multiple efflux pumps and target modifications. The bacterial type II topoisomerases DNA gyrase (GyrA2B2) and Topoisomerase IV (ParC2E2) are highly conserved targets across all bacterial species and validated in the clinic by the fluoroquinolones. Dual inhibitors targeting the ATPase domains (GyrB/ParE) of type II topoisomerases can overcome target-based fluoroquinolone resistance. However, few ATPase inhibitors are active against GN pathogens. In this study, we demonstrated a successful strategy to convert a 2-carboxamide substituted azaindole chemical scaffold with only Gram-positive (GP) activity into a novel series with also potent activity against a range of MDR GN pathogens. By systematically fine-tuning the many physicochemical properties, we identified lead compounds such as 17r with a balanced profile showing potent GN activity, high aqueous solubility, and desirable PK features. Moreover, we showed the bactericidal efficacy of 17r using a neutropenic mouse thigh infection model. Discovery of Pyrido[2,3-b]indole Derivatives with Gram-Negative Activity Targeting Both DNA Gyrase and Topoisomerase IV.,Hu Y, Shi H, Zhou M, Ren Q, Zhu W, Zhang W, Zhang Z, Zhou C, Liu Y, Ding X, Shen HC, Yan SF, Dey F, Wu W, Zhai G, Zhou Z, Xu Z, Ji Y, Lv H, Jiang T, Wang W, Xu Y, Vercruysse M, Yao X, Mao Y, Yu X, Bradley K, Tan X J Med Chem. 2020 Aug 24. doi: 10.1021/acs.jmedchem.0c00768. PMID:32787097[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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