Hidden suppressive interactions are common in higher-order drug combinations

The rapid increase of multi-drug resistant bacteria has led to a greater emphasis on multi-drug combination treatments. However, some combinations can be suppressive—that is, bacteria grow faster in some drug combinations than when treated with a single drug. Typically, when studying interactions, the overall effect of the combination is only compared to the single drug effects. However, doing so could miss “hidden” cases of suppression, which occur when the highest-order is suppressive compared to a lower-order combination but not to a single drug. We examined an extensive dataset of 5-drug combinations and all lower-order—single, 2-, 3-, and 4-drug—combinations. We found that a majority of all combinations—54%—contain hidden suppression. Examining hidden interactions is critical to understanding the architecture of higher-order interactions and can substantially affect our understanding and predictions of the evolution of antibiotic resistance under multi-drug treatments.

多重耐药细菌的快速蔓延，使得多药联合治疗方案受到了愈发广泛的重视。然而部分药物联合方案反而具有促生长效应——换言之，相较于单一药物治疗，部分药物联合使用时细菌的增殖速度更快。通常而言，在研究药物相互作用时，学界仅会将联合用药的整体效应与单一药物的药效进行对比，但这一研究范式可能会遗漏“隐性促生长”案例：当最高阶药物组合的促生长效应高于低阶联合用药，但与单一药物治疗相比并无显著差异时，这类情况便会被忽略。本研究针对涵盖5种药物组合及所有低阶组合（单一药物、二联、三联及四联药物组合）的大型数据集开展了分析。研究结果显示，全部组合中超过半数（54%）均存在隐性促生长现象。对隐性药物相互作用的解析，对于理解高阶药物相互作用的构成模式至关重要，同时也将极大地影响我们对多药联合治疗背景下抗生素耐药性演化过程的认知与预测能力。