4jlf

Inhibitor resistant (R220A) substitution in the Mycobacterium tuberculosis beta-lactamaseInhibitor resistant (R220A) substitution in the Mycobacterium tuberculosis beta-lactamase

Structural highlights 4jlf is a 1 chain structure with sequence from "bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: Related: 2gdn Gene: blaA, blaC, Rv2068c, MT2128, MTCY49.07c ("Bacillus tuberculosis" (Zopf 1883) Klein 1884) Activity: Beta-lactamase, with EC number 3.5.2.6 Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed The current emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis calls for novel treatment strategies. Recently, BlaC, the principal beta-lactamase of Mycobacterium tuberculosis, was recognized as a potential therapeutic target. The combination of meropenem and clavulanic acid, which inhibits BlaC, was found to be effective against even extensively drug-resistant M. tuberculosis strains when tested in vitro. Yet there is significant concern that drug resistance against this combination will also emerge. To investigate the potential of BlaC to evolve variants resistant to clavulanic acid, we introduced substitutions at important amino acid residues of M. tuberculosis BlaC (R220, A244, S130, and T237). Whereas the substitutions clearly led to in vitro clavulanic acid resistance in enzymatic assays but at the expense of catalytic activity, transformation of variant BlaCs into an M. tuberculosis H37Rv background revealed that impaired inhibition of BlaC did not affect inhibition of growth in the presence of ampicillin and clavulanate. From these data we propose that resistance to beta-lactam-beta-lactamase inhibitor combinations will likely not arise from structural alteration of BlaC, therefore establishing confidence that this therapeutic modality can be part of a successful treatment regimen against M. tuberculosis. Can inhibitor-resistant substitutions in the Mycobacterium tuberculosis beta-Lactamase BlaC lead to clavulanate resistance?: a biochemical rationale for the use of beta-lactam-beta-lactamase inhibitor combinations.,Kurz SG, Wolff KA, Hazra S, Bethel CR, Hujer AM, Smith KM, Xu Y, Tremblay LW, Blanchard JS, Nguyen L, Bonomo RA Antimicrob Agents Chemother. 2013 Dec;57(12):6085-96. doi: 10.1128/AAC.01253-13. , Epub 2013 Sep 23. PMID:24060876 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta-lactamase

spinqualitylabelsall models 4jlf, resolution 2.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image