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4-hydroxy-2-pyridones, a novel class of promising direct inhA inhibitors active against tuberculosis.

Manjunatha, Ujjini Havaldar and Rao, Srinivasa P.S. and Kondreddi, Ravinder Reddy and Noble, Christian Guy and Camacho, Luis and Tan, Bee Huat and Ng, Pearly and Kalapala, sarath and Ng, Ma and Lakshminarayana, Suresh Bangalore and Ng, Seow Hwee and Herve, Maxime Marcel and Kuhen, Kelli and Blasco, Francesca and Beer, David John and Walker, John and Glynne, Richard and Tonge, Peter and Smith, Paul William and Diagana, Thierry Tidiane (2015) 4-hydroxy-2-pyridones, a novel class of promising direct inhA inhibitors active against tuberculosis. Science Translational Medicine, 7 (269).

Abstract

Multi-drug resistant tuberculosis continues to be a major public health threat, particularly in the developing world. New chemotherapeutic agents are urgently required to combat the TB menace. We identified 4-hydroxy-2-pyridones, a new class of small molecules active against Mtb through phenotypic high-throughput screen. A lead candidate, NITD-916, is a potent bactericidal agent with a promising safety profile. NITD-916 demonstrated a dose dependent efficacy in vivo in acute and established mouse-infection models. Mechanism of-action studies identified the molecular target of NITD-916 as enoyl reductase (InhA), the clinically validated target of isoniazid and ethionamide. ITC and X-ray crystallography revealed that NITD-916 specifically binds to InhA in a NADH-dependent manner and blocks the lipid-substrate binding pocket. The NITD-916 co-crystal structure with InhA has opened-up new avenues for structure-guided rational drug discovery on a phenotypic-screening hit. Isoniazid resistant TB clinical isolates that are most frequently encountered remain fully susceptible to NITD-916, demonstrating the potential use of 4-hydroxy-2-pyridones against MDR-TB.

Item Type: Article
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/21471

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