title: Towards a new tuberculosis drug: pyridomycin - nature's isoniazid.
abstract: Tuberculosis, a global threat to public health, is becoming untreatable due to widespread drug resistance to frontline drugs such as the InhA-inhibitor isoniazid. Historically, by inhibiting highly vulnerable targets, natural products have been an important source of antibiotics including potent anti-tuberculosis agents. Here, we describe pyridomycin, a compound produced by Dactylosporangium fulvum with specific cidal activity against mycobacteria. By selecting pyridomycin-resistant mutants of Mycobacterium tuberculosis, whole-genome sequencing and genetic validation, we identified the NADH-dependent enoyl- (Acyl-Carrier-Protein) reductase InhA as the principal target and demonstrate that pyridomycin inhibits mycolic acid synthesis in M. tuberculosis. Furthermore, biochemical and structural studies show that pyridomycin inhibits InhA directly as a competitive inhibitor of the NADH-binding site, thereby identifying a new, druggable pocket in InhA. Importantly, the most frequently encountered isoniazid-resistant clinical isolates remain fully susceptible to pyridomycin, thus opening new avenues for drug development. →See accompanying article http://dx.doi.org/10.1002/emmm.201201811.
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne, Global Health Institute, Lausanne, Switzerland.
authors.forename: Ruben C
authors.initials: RC
authors.lastname: Hartkoorn
authors.forename: Claudia
authors.initials: C
authors.lastname: Sala
authors.forename: João
authors.initials: J
authors.lastname: Neres
authors.forename: Florence
authors.initials: F
authors.lastname: Pojer
authors.forename: Sophie
authors.initials: S
authors.lastname: Magnet
authors.forename: Raju
authors.initials: R
authors.lastname: Mukherjee
authors.forename: Swapna
authors.initials: S
authors.lastname: Uplekar
authors.forename: Stefanie
authors.initials: S
authors.lastname: Boy-Röttger
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Altmann
authors.forename: Stewart T
authors.initials: ST
authors.lastname: Cole
mesh_terms: D000995:Antitubercular Agents / Q000302:isolation & purification / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D001688:Biological Products / Q000302:isolation & purification / Q000494:pharmacology*; D053898:Biosynthetic Pathways / Q000187:drug effects; D024881:Drug Resistance, Bacterial; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000494:pharmacology; D008848:Micromonosporaceae / Q000737:chemistry*; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009171:Mycolic Acids / Q000378:metabolism; D009842:Oligopeptides / Q000302:isolation & purification / Q000494:pharmacology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D012641:Selection, Genetic
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D001688:Biological Products; D004791:Enzyme Inhibitors; D009171:Mycolic Acids; D009842:Oligopeptides; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium; C458999:pyridomycin