6M1S
The DNA Gyrase B ATP binding domain of PSEUDOMONAS AERUGINOSA in complex with compound 12o
Summary for 6M1S
| Entry DOI | 10.2210/pdb6m1s/pdb |
| Descriptor | DNA gyrase subunit B, 3-[5-[8-(ethylamino)-6-fluoranyl-4-[3-(trifluoromethyl)pyrazol-1-yl]-9H-pyrido[2,3-b]indol-3-yl]pyrimidin-2-yl]oxy-2,2-dimethyl-propanoic acid, SULFATE ION, ... (5 entities in total) |
| Functional Keywords | dna gyrase, topoisomerase, atpase domain, isomerase |
| Biological source | Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) |
| Total number of polymer chains | 2 |
| Total formula weight | 49197.00 |
| Authors | |
| Primary citation | Hu, Y.,Shi, H.,Zhou, M.,Ren, Q.,Zhu, W.,Zhang, W.,Zhang, Z.,Zhou, C.,Liu, Y.,Ding, X.,Shen, H.C.,Yan, S.F.,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. Discovery of Pyrido[2,3-b]indole Derivatives with Gram-Negative Activity Targeting Both DNA Gyrase and Topoisomerase IV. J.Med.Chem., 63:9623-9649, 2020 Cited by PubMed Abstract: The 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 (GyrAB) and Topoisomerase IV (ParCE) 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 with a balanced profile showing potent GN activity, high aqueous solubility, and desirable PK features. Moreover, we showed the bactericidal efficacy of using a neutropenic mouse thigh infection model. PubMed: 32787097DOI: 10.1021/acs.jmedchem.0c00768 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.254 Å) |
Structure validation
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