Yang B, Koga H, Ohno H, Ogawa K, Fukuda M, Hirakata Y, Maesaki S, Tomono K, Tashiro T, Kohno S
The Second Department of Internal Medicine, Nagasaki University School of Medicine, Japan.
J Antimicrob Chemother. 1998 Nov;42(5):621-8. doi: 10.1093/jac/42.5.621.
We compared the in-vitro antimycobacterial activities of rifabutin and KRM-1648, two rifamycin derivatives, with that of rifampicin against 163 strains of Mycobacterium tuberculosis. We also evaluated the correlation between the level of resistance to rifampicin, rifabutin and KRM-1648 and genetic alterations in the rpoB gene. All 82 strains susceptible to rifampicin or resistant to rifampicin with MICs < or = 16 mg/L were susceptible to rifabutin and KRM-1648 with MICs < or = 1 mg/L. Seventy-six of 81 strains resistant to rifampicin with MICs > or = 32 mg/L were resistant to both rifabutin and KRM-1648, but with lower MICs than those of rifampicin. KRM-1648 showed more potent antimycobacterial activity than rifabutin against organisms with low MICs (< or = 1 mg/L), while rifabutin was more active than KRM-1648 against organisms with high MICs (> or = 2 mg/L). A total of 96 genetic alterations around the 69 bp core region of the rpoB gene were detected in 92 strains. Alterations at codons 515, 521 and 533 in the rpoB gene did not influence the susceptibility to rifampicin, rifabutin and KRM-1648. Point mutations at codons 516 and 529, deletion at codon 518 and insertion at codon 514 influenced the susceptibility to rifampicin but not that to rifabutin or KRM-1648. With the exception of one strain, all alterations at codon 513 and 531 correlated with resistance to the three test drugs. The resistant phenotype of strains with an alteration at codon 526 depended on the type of amino acid substitution. Our results suggest that analysis of genetic alterations in the rpoB gene might be useful not only for predicting rifampicin susceptibility, but also for deciding when to use rifabutin for treating tuberculosis. Further studies may be required to determine the usefulness of KRM-1648.
我们比较了利福布汀和KRM - 1648这两种利福霉素衍生物与利福平对163株结核分枝杆菌的体外抗分枝杆菌活性。我们还评估了对利福平、利福布汀和KRM - 1648的耐药水平与rpoB基因遗传改变之间的相关性。所有82株对利福平敏感或对利福平耐药且MICs≤16mg/L的菌株对利福布汀和KRM - 1648敏感，其MICs≤1mg/L。81株对利福平耐药且MICs≥32mg/L的菌株中有76株对利福布汀和KRM - 1648均耐药，但它们对这两种药物的MICs低于对利福平的MICs。KRM - 1648对低MICs（≤1mg/L）的菌株显示出比利福布汀更强的抗分枝杆菌活性，而利福布汀对高MICs（≥2mg/L）的菌株比KRM - 1648更具活性。在92株菌株中总共检测到rpoB基因69bp核心区域周围96处遗传改变。rpoB基因中第515、521和533密码子的改变不影响对利福平、利福布汀和KRM - 1648的敏感性。第516和529密码子的点突变、第518密码子的缺失以及第514密码子的插入影响对利福平的敏感性，但不影响对利福布汀或KRM - 1648的敏感性。除1株菌株外，第513和531密码子的所有改变均与对这三种受试药物的耐药性相关。第526密码子发生改变的菌株的耐药表型取决于氨基酸替代的类型。我们的结果表明，分析rpoB基因的遗传改变可能不仅有助于预测利福平敏感性，还能用于决定何时使用利福布汀治疗结核病。可能需要进一步研究以确定KRM - 1648的实用性。
