Collateral Resistance and Sensitivity Modulate Evolution of High-Level Resistance to Drug Combination Treatment in Staphylococcus aureus
Collateral Resistance and Sensitivity Modulate Evolution of High-Level Resistance to Drug Combination Treatment in Staphylococcus aureus
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DOI：
10.1093/molbev/msv006
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发表时间：
2015-05-01
影响因子：
10.7
通讯作者：
Sommer, Morten O. A.
中科院分区：
文献类型：
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作者：
de Evgrafov, Mari Rodriguez;Gumpert, Heidi;Sommer, Morten O. A.
随着耐药病原体的不断出现，将越来越多地依赖联合治疗来治疗感染，并帮助对抗多药耐药性的进一步发展。目前，在临床实践和科学模型之间存在着二分法，前者有利于治疗协同组合，而后者则认为这种相互作用比其他相互作用类型提供了更大的耐药性发展选择压力。我们试图扩展目前的范例，根据工作低于或接近最低抑菌浓度水平，以反映药物浓度更有可能在治疗过程中遇到的。我们使用金黄色葡萄球菌进行了一系列的自适应进化实验。有趣的是，没有发现药物相互作用类型和耐药性演变之间的关系，因为耐药性显著增加超过野生型水平。与单药治疗相比，所有药物组合，无论相互作用类型如何，均有效限制了耐药性演变。交叉耐药和侧枝敏感性被认为是耐药演变的程度向组合的重要因素。比较基因组分析显示，药物组合的耐药性主要是由单一药物进化谱系相同基因的突变介导的，这突出了组分药物在确定耐药性进化速率中的重要性。这项工作的结果表明，耐药机制的组成药物应是未来的耐药进化工作的重点。
As drug-resistant pathogens continue to emerge, combination therapy will increasingly be relied upon to treat infections and to help combat further development of multidrug resistance. At present a dichotomy exists between clinical practice, which favors therapeutically synergistic combinations, and the scientific model emerging from in vitro experimental work, which maintains that this interaction provides greater selective pressure toward resistance development than other interaction types. We sought to extend the current paradigm, based on work below or near minimum inhibitory concentration levels, to reflect drug concentrations more likely to be encountered during treatment. We performed a series of adaptive evolution experiments using Staphylococcus aureus. Interestingly, no relationship between drug interaction type and resistance evolution was found as resistance increased significantly beyond wild-type levels. All drug combinations, irrespective of interaction types, effectively limited resistance evolution compared with monotreatment. Cross-resistance and collateral sensitivity were found to be important factors in the extent of resistance evolution toward a combination. Comparative genomic analyses revealed that resistance to drug combinations was mediated largely by mutations in the same genes as single-drug-evolved lineages highlighting the importance of the component drugs in determining the rate of resistance evolution. Results of this work suggest that the mechanisms of resistance to constituent drugs should be the focus of future resistance evolution work.