7U0O

Crystal structure of an enoyl-[acyl-carrier-protein] reductase InhA from Mycobacterium fortuitum bound to NAD and NITD-916

Summary for 7U0O

• Entry DOI: 10.2210/pdb7u0o/pdb
• Descriptor: Enoyl-[acyl-carrier-protein] reductase [NADH], NICOTINAMIDE-ADENINE-DINUCLEOTIDE, 6-[(4,4-dimethylcyclohexyl)methyl]-4-hydroxy-3-phenylpyridin-2(1H)-one, ... (6 entities in total)
• Functional Keywords: inha, mycobacterium, pulmonary infection, cf, nad-depdendent enzyme, structural genomics, seattle structural genomics center for infectious disease, ssgcid, oxidoreductase
• Biological source: Mycolicibacterium fortuitum
• Total number of polymer chains: 2
• Total formula weight: 60880.10

Authors

Seattle Structural Genomics Center for Infectious Disease,Seattle Structural Genomics Center for Infectious Disease (SSGCID) (deposition date: 2022-02-18, release date: 2023-02-22, Last modification date: 2023-10-25)

Primary citation

Roquet-Baneres, F.,Alcaraz, M.,Hamela, C.,Abendroth, J.,Edwards, T.E.,Kremer, L.
In Vitro and In Vivo Efficacy of NITD-916 against Mycobacterium fortuitum.
Antimicrob.Agents Chemother., 67:e0160722-e0160722, 2023

PubMed Abstract: 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 synthesis of mycolic acids. Resolving the crystal structure of the InhA in complex with NAD and NITD-916 confirmed that NITD-916 is a direct inhibitor of InhA. Importantly, single nucleotide polymorphism leading to a G96S substitution in InhA 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 and and should be considered in future preclinical evaluations for the treatment of M. fortuitum pulmonary diseases.

PubMed: 36920188
DOI: 10.1128/aac.01607-22

Experimental method

X-RAY DIFFRACTION (2.05 Å)