6zgm

Crystal Structure of the VIM-2 Acquired Metallo-beta-Lactamase in Complex with the thiazolecarboxylate inhibitor ANT2681

spinqualitylabelsall models 6zgm, resolution 1.65Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6zgm is a 1 chain structure with sequence from Pseudomonas aeruginosa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.65Å Ligands: ACT, QKK, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q9K2N0_PSEAI Publication Abstract from PubMed The clinical effectiveness of the important beta-lactam class of antibiotics is under threat by the emergence of resistance, mostly due to the production of acquired serine- (SBL) and metallo-beta-lactamase (MBL) enzymes. To address this resistance issue, multiple beta-lactam/beta-lactamase inhibitor combinations have been successfully introduced into the clinic over the past several decades. However, all of those combinations contain SBL inhibitors and, as yet, there are no MBL inhibitors in clinical use. Consequently, there exists an unaddressed yet growing healthcare problem due to the rise in recent years of highly resistant strains which produce New Delhi metallo (NDM)-type metallo-carbapenemases. Previously, we reported the characterization of an advanced MBL inhibitor lead compound, ANT431. Herein, we discuss the completion of a lead optimization campaign culminating in the discovery of the preclinical candidate ANT2681, a potent NDM inhibitor with strong potential for clinical development. ANT2681: SAR Studies Leading to the Identification of a Metallo-beta-lactamase Inhibitor with Potential for Clinical Use in Combination with Meropenem for the Treatment of Infections Caused by NDM-Producing Enterobacteriaceae.,Davies DT, Leiris S, Sprynski N, Castandet J, Lozano C, Bousquet J, Zalacain M, Vasa S, Dasari PK, Pattipati R, Vempala N, Gujjewar S, Godi S, Jallala R, Sathyap RR, Darshanoju NA, Ravu VR, Juventhala RR, Pottabathini N, Sharma S, Pothukanuri S, Holden K, Warn P, Marcoccia F, Benvenuti M, Pozzi C, Mangani S, Docquier JD, Lemonnier M, Everett M ACS Infect Dis. 2020 Aug 20. doi: 10.1021/acsinfecdis.0c00207. PMID:32786279 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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