Epistasis between antibiotic resistance mutations drives the evolution of extensively drug-resistant tuberculosis.
Epistasis between antibiotic resistance mutations drives the evolution of extensively drug-resistant tuberculosis.
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DOI：
10.1093/emph/eot003
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发表时间：
2013-01
期刊：
影响因子：
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通讯作者：
Gagneux S
中科院分区：
文献类型：
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作者：
Borrell S;Teo Y;Giardina F;Streicher EM;Klopper M;Feldmann J;Müller B;Victor TC;Gagneux S
作者表明，一些携带对两种抗生素具有抗性的突变的分枝杆菌比仅携带其中一种突变的相应菌株具有更高的竞争适合度。此外，在实验室中表现出最高竞争适应性的双重耐药菌株在具有高负担的广泛耐药结核病的临床环境中的代表性过高。背景和目的：多重耐药（MDR）细菌对全球健康的威胁日益严重。针对单一抗生素的研究表明，在没有药物的情况下，耐药性往往与健康成本有关。然而，人们对与对多种抗生素的耐药性相关的健身成本知之甚少。方法学：我们使用耻垢分枝杆菌作为人类结核病（TB）的模型和体外竞争适应性试验，以探索联合适应性效应和突变之间的相互作用，从而对利福平（RIF）和氧氟沙星（OFX）产生耐药性;这两种药物分别是最重要的一线和二线抗结核药物。结果：17例M.当假设每个个体突变的适应性效应的乘法模型时，耐RIF和OFX的耻垢病突变体（24%）显示出统计学上显著高于或低于预期的竞争适应性。此外，17个双耐药突变体中的6个（35%）比相应的单耐药突变体中的至少一个具有显著更高的适应度。抗性突变的特定组合与M.在来自南非的151株MDR和广泛耐药（XDR）结核分枝杆菌临床分离株中，结论和影响：我们的研究结果表明，分枝杆菌耐药突变之间的上位性可以导致MDR菌株没有健身赤字，这些菌株是积极选择的耐药结核病的高负担的设置。综上所述，我们的研究结果支持上位性在耐多药和广泛耐药结核病的演变和流行病学中的作用。
The authors show that some mycobacteria carrying mutations conferring resistance to two antibiotics have a higher competitive fitness than corresponding strains carrying only one of these mutations. Moreover, the double-resistant strains exhibiting the highest competitive fitness in the laboratory are overrepresented in clinical settings with a high burden of extensively drug-resistant tuberculosis. Background and objectives: Multidrug resistant (MDR) bacteria are a growing threat to global health. Studies focusing on single antibiotics have shown that drug resistance is often associated with a fitness cost in the absence of drug. However, little is known about the fitness cost associated with resistance to multiple antibiotics. Methodology: We used Mycobacterium smegmatis as a model for human tuberculosis (TB) and an in vitro competitive fitness assay to explore the combined fitness effects and interaction between mutations conferring resistance to rifampicin (RIF) and ofloxacin (OFX); two of the most important first- and second-line anti-TB drugs, respectively. Results: We found that 4 out of 17 M. smegmatis mutants (24%) resistant to RIF and OFX showed a statistically significantly higher or lower competitive fitness than expected when assuming a multiplicative model of fitness effects of each individual mutation. Moreover, 6 out of the 17 double drug-resistant mutants (35%) had a significantly higher fitness than at least one of the corresponding single drug-resistant mutants. The particular combinations of resistance mutations associated with no fitness deficit in M. smegmatis were the most frequent among 151 clinical isolates of MDR and extensively drug-resistant (XDR) Mycobacterium tuberculosis from South Africa. Conclusions and implications: Our results suggest that epistasis between drug resistance mutations in mycobacteria can lead to MDR strains with no fitness deficit, and that these strains are positively selected in settings with a high burden of drug-resistant TB. Taken together, our findings support a role for epistasis in the evolution and epidemiology of MDR- and XDR-TB.