Mariam Deneke H, Mengistu Yohannes, Hoffner Sven E, Andersson Dan I
Department of Bacteriology, Swedish Institute for Infectious Disease Control, S-171 82 Solna, Sweden.
Antimicrob Agents Chemother. 2004 Apr;48(4):1289-94. doi: 10.1128/AAC.48.4.1289-1294.2004.
Rifampin is a major drug used in the treatment of tuberculosis infections, and increasing rifampin resistance represents a worldwide clinical problem. Resistance to rifampin is caused by mutations in the rpoB gene, encoding the beta-subunit of RNA polymerase. We examined the effect of three different rpoB mutations on the fitness of Mycobacterium tuberculosis. Rifampin-resistant mutants were isolated from a virulent clinical isolate of M. tuberculosis (strain Harlingen) in vitro at a mutation frequency of 2.3 x 10(-8). Mutations in the rpoB gene were identified, and the growth rates of three defined mutants were measured by competition with the susceptible parent strain in laboratory medium and by single cultures in a macrophage cell line and in laboratory medium. All of the mutants showed a decreased growth rate in the three assays. The relative fitness of the mutants varied between 0.29 and 0.96 (that of the susceptible strain was set to 1.0) depending on the specific mutant and assay system. Unexpectedly, the relative fitness ranking of the mutants differed between the different assays. In conclusion, rifampin resistance is associated with a cost that is conditional.
利福平是治疗结核感染的主要药物，而利福平耐药性的增加是一个全球性的临床问题。对利福平的耐药性是由编码RNA聚合酶β亚基的rpoB基因突变引起的。我们研究了三种不同的rpoB突变对结核分枝杆菌适应性的影响。从一株强毒力的结核分枝杆菌临床分离株（哈林根菌株）中体外分离出利福平耐药突变体，突变频率为2.3×10⁻⁸。鉴定了rpoB基因中的突变，并通过在实验室培养基中与敏感亲本菌株竞争以及在巨噬细胞系和实验室培养基中进行单培养来测量三个确定突变体的生长速率。所有突变体在这三种测定中均显示出生长速率下降。根据具体的突变体和测定系统，突变体的相对适应性在0.29至0.96之间（将敏感菌株的相对适应性设定为1.0）。出乎意料的是，不同测定之间突变体的相对适应性排名不同。总之，利福平耐药性与一种有条件的代价相关。
