Hidden suppressive interactions are common in higher-order drug combinations

• Main Authors: Natalie Ann Lozano-Huntelman, April Zhou, Elif Tekin, Mauricio Cruz-Loya, Bjørn Østman, Sada Boyd, Van M. Savage, Pamela Yeh
• Format: Article
• Language: English
• Published: Elsevier 2021-04-01
• Series: iScience
• Subjects: Microbiology; Systems Biology
• Online Access: http://www.sciencedirect.com/science/article/pii/S2589004221003230

Summary: 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 with the single-drug effects. However, doing so could miss “hidden” cases of suppression, which occur when the highest order is suppressive compared with 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.