Molecular genetic basis of antimicrobial agent resistance in Mycobacterium tuberculosis: 1998 update
Molecular genetic basis of antimicrobial agent resistance in Mycobacterium tuberculosis: 1998 update
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DOI：
10.1054/tuld.1998.0002
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发表时间：
1998-01-01
期刊：
影响因子：
--
通讯作者：
Musser, James M.
中科院分区：
文献类型：
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作者：
Ramaswamy, S.;Musser, James M.
自从我们三年前回顾这一主题以来，对抗结核药物耐药性的分子遗传学基础的了解已经迅速发展。事实上，所有对利福平和相关利福霉素耐药的分离株都存在突变，该突变会改变核糖核酸 (RNA) 聚合酶 β 亚基的 27 个氨基酸区域的序列。对异烟肼 (INH) 的耐药性更为复杂。许多抗性生物体的编码过氧化氢酶-过氧化物酶的 katG 基因发生突变，导致酶结构改变。这些结构变化显然导致 INH 向生物活性形式的转化减少。一些 INH 抗性生物体的 inhA 基因座或最近鉴定的编码 β-酮酰基-酰基载体蛋白合酶的基因 (kasA) 也有突变。链霉素耐药性主要是由于 16S rRNA 基因或编码核糖体蛋白 S12 的 rpsL 基因突变所致。绝大多数生物体对吡嗪酰胺的抗性是由编码吡嗪酰胺酶的基因 (pncA) 突变引起的，导致酶活性降低。大约 60% 的生物体中的乙胺丁醇抗性是由于 embB 基因编码的阿拉伯糖基转移酶的 306 位氨基酸替换所致。脱氧核糖核酸促旋酶 A 亚基的氨基酸变化会导致大多数生物体对氟喹诺酮类药物产生耐药性。卡那霉素耐药性是由于编码 16S rRNA 的 rrs 基因中的核苷酸取代造成的。多重耐药菌株是由于单个药物耐药突变的连续积累而产生的。有限的证据表明，一些具有严重改变过氧化氢酶-过氧化物酶活性的突变的耐药菌株在动物模型中毒性较低。有多种策略可帮助快速检测耐药相关基因突变。尽管已经取得了显着的进展，但关于结核分枝杆菌耐药性的分子遗传基础仍有很多知识有待了解。有理由相信，基于从耐药分子机制研究中获得的知识，新疗法的开发将会出现。
Knowledge of the molecular genetic basis of resistance to antituberculous agents has advanced rapidly since we reviewed this topic 3 years ago. Virtually all isolates resistant to rifampin and related rifamycins have a mutation that alters the sequence of a 27-amino-acid region of the beta subunit of ribonucleic acid (RNA) polymerase. Resistance to isoniazid (INH) is more complex. Many resistant organisms have mutations in the katG gene encoding catalase-peroxidase that result in altered enzyme structure. These structural changes apparently result in decreased conversion of INH to a biologically active form. Some INH-resistant organisms also have mutations in the inhA locus or a recently characterized gene (kasA) encoding a beta-ketoacyl-acyl carrier protein synthase. Streptomycin resistance is due mainly to mutations in the 16S rRNA gene or the rpsL gene encoding ribosomal protein S12. Resistance to pyrazinamide in the great majority of organisms is caused by mutations in the gene (pncA) encoding pyrazinamidase that result in diminished enzyme activity. Ethambutol resistance in approximately 60% of organisms is due to amino acid replacements at position 306 of an arabinosyltransferase encoded by the embB gene. Amino acid changes in the A subunit of deoxyribonucleic acid gyrase cause fluoroquinolone resistance in most organisms. Kanamycin resistance is due to nucleotide substitutions in the rrs gene encoding 16S rRNA. Multidrug resistant strains arise by sequential accumulation of resistance mutations for individual drugs. Limited evidence exists indicating that some drug resistant strains with mutations that severely alter catalase-peroxidase activity are less virulent in animal models. A diverse array of strategies is available to assist in rapid detection of drug resistance-associated gene mutations. Although remarkable advances have been made, much remains to be learned about the molecular genetic basis of drug resistance in Mycobacterium tuberculosis. It is reasonable to believe that development of new therapeutics based on knowledge obtained from the study of the molecular mechanisms of resistance will occur.