Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, People's Republic of China.
Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, People's Republic of China.
Antimicrob Agents Chemother. 2022 Dec 20;66(12):e0053122. doi: 10.1128/aac.00531-22. Epub 2022 Nov 30.
Delamanid (DLM) and pretomanid (PTM) are recent additions to the anti-tuberculosis (TB) drug armamentarium, and they offer more effective options for drug-resistant TB treatment. In particular, DLM is included in Group C, which is recommended for use in longer multidrug-resistant (MDR)-TB regimens. Previous studies have shown that resistance to DLM/PTM is caused by mutations in the , , , , , and genes, which are related to the F-dependent bioactivation pathway. Herein, we conduct selection of DLM-resistant strains using clinical Mycobacterium tuberculosis (MTB) isolates with various drug resistance profiles. The spontaneous resistance frequency of drug-susceptible (DS) MTB (1.14 × 10 to 1.04 × 10) to DLM was similar to that of H37Rv (8.88 × 10 to 9.96 × 10) but higher than those of multidrug-resistant MTB (2.03 × 10 to 3.18 × 10) and extensively drug-resistant (XDR) MTB (4.67 × 10 to 3.60 × 10). Of the 100 independently selected DLM-resistant MTB mutants, 65% harbored mutations in genes associated with either DLM prodrug activation (, 39.73%; , 16.44%) or the F biosynthetic pathway (, 16.44%; , 5.48%; , 21.92%). Of the 45 mutations we identified, 38 were not previously reported. A structure analysis revealed that several point mutations affected the ligand binding or structural stability of enzymes related to DLM resistance, which would block the enzyme activity required for prodrug activation. Our results elucidate the spontaneous DLM-resistance patterns of different clinical strains, which could improve the understanding of the causes of DLM resistance in clinical strains and of the effects on drug resistance of different mutations in genes that are related to the DLM activation pathway.
德拉马尼（DLM）和普托马尼（PTM）是抗结核（TB）药物武器库中的最新成员，它们为耐药性结核病治疗提供了更有效的选择。特别是，DLM 被列入 C 组，建议用于更长的耐多药（MDR）-TB 方案。先前的研究表明，对 DLM/PTM 的耐药性是由 、 、 、 、 和 基因的突变引起的，这些突变与 F 依赖性生物激活途径有关。在此，我们使用具有各种耐药谱的临床结核分枝杆菌（MTB）分离株进行 DLM 耐药株的选择性筛选。药敏 MTB（1.14×10 至 1.04×10）对 DLM 的自发耐药频率与 H37Rv（8.88×10 至 9.96×10）相似，但高于多药耐药 MTB（2.03×10 至 3.18×10）和广泛耐药 MTB（4.67×10 至 3.60×10）。在 100 个独立选择的 DLM 耐药 MTB 突变体中，65%的突变发生在与 DLM 前药激活（ ，39.73%； ，16.44%）或 F 生物合成途径（ ，16.44%； ，5.48%； ，21.92%）相关的基因中。在我们鉴定的 45 个突变中，有 38 个是以前没有报道过的。结构分析表明，几个点突变影响了与 DLM 耐药相关的酶的配体结合或结构稳定性，这将阻断前药激活所需的酶活性。我们的研究结果阐明了不同临床菌株中自发的 DLM 耐药模式，这可以提高我们对临床菌株中 DLM 耐药原因的理解，以及对与 DLM 激活途径相关的基因中不同突变对耐药性影响的理解。
