Hidden suppressive interactions are common in higher-order drug combinations

Natalie Ann Lozano-Huntelman; April Zhou; Elif Tekin; Mauricio Cruz-Loya; Bjørn Østman; Sada Boyd; Van M. Savage; Pamela Yeh

iScience (Apr 2021)

Hidden suppressive interactions are common in higher-order drug combinations

Natalie Ann Lozano-Huntelman,
April Zhou,
Elif Tekin,
Mauricio Cruz-Loya,
Bjørn Østman,
Sada Boyd,
Van M. Savage,
Pamela Yeh

Affiliations

Natalie Ann Lozano-Huntelman: Ecology and Evolutionary Biology, University of California, Los Angeles, 90095, USA
April Zhou: Ecology and Evolutionary Biology, University of California, Los Angeles, 90095, USA; Computational and Systems Biology, University of California, Los Angeles, 90095, USA
Elif Tekin: Ecology and Evolutionary Biology, University of California, Los Angeles, 90095, USA
Mauricio Cruz-Loya: Computational and Systems Biology, University of California, Los Angeles, 90095, USA
Bjørn Østman: Ecology and Evolutionary Biology, University of California, Los Angeles, 90095, USA
Sada Boyd: Ecology and Evolutionary Biology, University of California, Los Angeles, 90095, USA
Van M. Savage: Ecology and Evolutionary Biology, University of California, Los Angeles, 90095, USA; Computational and Systems Biology, University of California, Los Angeles, 90095, USA; Santa Fe Institute, Santa Fe, NM 87501, USA
Pamela Yeh: Ecology and Evolutionary Biology, University of California, Los Angeles, 90095, USA; Santa Fe Institute, Santa Fe, NM 87501, USA; Corresponding author

Journal volume & issue: Vol. 24, no. 4
p. 102355

Abstract

Read online

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.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

About the journal

Abstract

Keywords