7k73 | pdb_00007k73

Structure of Enoyl-[acyl-carrier-protein] reductase [NADH] from Mycobacterium fortuitum bound to NAD

spinqualitylabelsall models 7k73, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7k73 is a 4 chain structure with sequence from Mycolicibacterium fortuitum. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.8Å Ligands: ACT, EDO, NAD Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A0A0N9XSE6_MYCFO Publication Abstract from PubMed Mycobacterium fortuitum represents one of the most clinically relevant rapid-growing mycobacterial species. Treatments are complex due to antibiotic resistance and to severe side effects of effective drugs, prolonged time of treatment, and co-infection with other pathogens. Herein, we explored the activity of NITD-916, a direct inhibitor of the enoyl-ACP reductase InhA of the type II fatty acid synthase in Mycobacterium tuberculosis. We found that this compound displayed very low MIC values against a panel of M. fortuitum clinical strains and exerted potent antimicrobial activity against M. fortuitum in macrophages. Remarkably, the compound was also highly efficacious in a zebrafish model of infection. Short duration treatments were sufficient to significantly protect the infected larvae from M. fortuitum-induced killing, which correlated with reduced bacterial burdens and abscesses. Biochemical analyses demonstrated an inhibition of de novo synthesis of mycolic acids. Resolving the crystal structure of the InhA(MFO) in complex with NAD and NITD-916 confirmed that NITD-916 is a direct inhibitor of InhA(MFO). Importantly, single nucleotide polymorphism leading to a G96S substitution in InhA(MFO) conferred high resistance levels to NITD-916, thus resolving its target in M. fortuitum. Overall, these findings indicate that NITD-916 is highly active against M. fortuitum both in vitro and in vivo and should be considered in future preclinical evaluations for the treatment of M. fortuitum pulmonary diseases. In Vitro and In Vivo Efficacy of NITD-916 against Mycobacterium fortuitum.,Roquet-Baneres F, Alcaraz M, Hamela C, Abendroth J, Edwards TE, Kremer L Antimicrob Agents Chemother. 2023 Mar 15:e0160722. doi: 10.1128/aac.01607-22. PMID:36920188 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Enoyl-Acyl-Carrier Protein Reductase 3D structures

Proteopedia Page Contributors and Editors (what is this?)

OCA