Ecole Polytechnique Fédérale de Lausanne, Global Health Institute, Lausanne, Switzerland.
EMBO Mol Med. 2012 Oct;4(10):1032-42. doi: 10.1002/emmm.201201689. Epub 2012 Sep 17.
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.
结核病是全球公共卫生的一大威胁，由于一线药物（如 InhA 抑制剂异烟肼）的广泛耐药性，这种疾病变得难以治疗。历史上，天然产物通过抑制高度脆弱的靶标，一直是抗生素的重要来源，包括强效的抗结核药物。在这里，我们描述了由 Dactylosporangium fulvum 产生的吡啶霉素，它对分枝杆菌具有特定的杀菌活性。通过选择结核分枝杆菌的吡啶霉素抗性突变体，进行全基因组测序和遗传验证，我们确定 NADH 依赖性烯酰基（酰基载体蛋白）还原酶 InhA 是主要靶标，并证明吡啶霉素抑制分枝杆菌中的分枝酸合成。此外，生化和结构研究表明，吡啶霉素通过竞争性抑制 NADH 结合位点直接抑制 InhA，从而在 InhA 中鉴定出一个新的、可成药的口袋。重要的是，最常见的异烟肼耐药临床分离株仍然对吡啶霉素完全敏感，从而为药物开发开辟了新的途径。→参见伴随文章，http://dx.doi.org/10.1002/emmm.201201811。
