Ohno H, Koga H, Kohno S
Second Department of Internal Medicine, Nagasaki University School of Medicine, Japan.
Kekkaku. 1998 Nov;73(11):657-63.
Multidrug-resistant Mycobacterium tuberculosis infection is now world wide health problem. However, according to the recent advances of molecular biological technics, some of the genetic mechanisms of drug-resistance of M. tuberculosis has been uncovered. Generally, drug-resistance of M. tuberculosis was caused by point mutations in chromosomal gene. In isoniazid (INH) resistant M. tuberculosis, mutations and genetic deletions in catalase-peroxidase gene (katG), inhA gene, or alkyl hydroperoxide reductase gene were reported. We also found that about 15% of INH-resistant M. tuberculosis isolates lacked katG gene, and these isolates showed highly resistance to INH with MIC > or = 64 micrograms/ml. On the other hand, mutations and other genetic alterations in RNA polymerase beta subunit gene (rpoB) were the major mechanisms of resistance to rifampicin (RFP) with high frequencies of 90% or more. Our evaluation of the relationship between RFP susceptibility and genetic alteration in rpoB gene also showed that 95% of RFP-resistant M. tuberculosis isolates involved genetic alterations in 69 bp core region of rpoB gene. Moreover, these genetic alterations in rpoB gene were suspected as the resistant mechanism to other rifamycin antituberculosis drugs, such as rifabutin and KRM-1648. In addition, it was reported that point mutations in 16S rRNA gene (rrs) and ribosomal protein S12 gene (rpsL) induced M. tuberculosis as streptomycin (SM) resistant phenotype. We analyzed genetic alternations in rpsL gene of clinically isolates of M. tuberculosis, about 60% of SM resistant isolates were shown point mutation in this gene ant they were all high SM-resistant with MIC > or = 256 micrograms/ml. Furthermore, nicotinamidase (pncA) gene, DNA gyrase A subunit (gyrA) gene, and embB gene were reported as the responsible gene to pyrazinamide-, quinolone- and ethambutol-resistance, respectively. Although all mechanisms of drug-resistance were still unclear, these informations are very useful and helpful for development of rapid diagnosis system of drug-resistant M. tuberculosis.
耐多药结核分枝杆菌感染现已成为全球性的健康问题。然而，根据分子生物学技术的最新进展，结核分枝杆菌耐药的一些遗传机制已被揭示。一般来说，结核分枝杆菌的耐药性是由染色体基因突变引起的。在耐异烟肼（INH）的结核分枝杆菌中，已报道过氧化氢酶-过氧化物酶基因（katG）、inhA基因或烷基过氧化氢还原酶基因发生突变和基因缺失。我们还发现，约15%的耐INH结核分枝杆菌分离株缺乏katG基因，这些分离株对INH表现出高度耐药，MIC≥64微克/毫升。另一方面，RNA聚合酶β亚基基因（rpoB）的突变和其他基因改变是对利福平（RFP）耐药的主要机制，频率高达90%或更高。我们对RFP敏感性与rpoB基因遗传改变之间关系的评估还表明，95%的耐RFP结核分枝杆菌分离株涉及rpoB基因69bp核心区域的遗传改变。此外，rpoB基因的这些遗传改变被怀疑是对其他利福霉素抗结核药物（如利福布汀和KRM-1648）的耐药机制。此外，据报道16S rRNA基因（rrs）和核糖体蛋白S12基因（rpsL）的点突变诱导结核分枝杆菌产生链霉素（SM）耐药表型。我们分析了临床分离的结核分枝杆菌rpsL基因的遗传改变，约60%的耐SM分离株在该基因中出现点突变，它们对SM均具有高度耐药性，MIC≥256微克/毫升。此外，烟酰胺酶（pncA）基因、DNA回旋酶A亚基（gyrA）基因和embB基因分别被报道为对吡嗪酰胺、喹诺酮和乙胺丁醇耐药的相关基因。虽然所有耐药机制仍不清楚，但这些信息对于开发耐多药结核分枝杆菌的快速诊断系统非常有用且有帮助。
