Prediction of resistance development against drug combinations by collateral responses to component drugs.
Resistance arises quickly during chemotherapeutic selection and is particularly problematic during long-term treatment regimens such as those for tuberculosis, HIV infections, or cancer. Although drug combination therapy reduces the evolution of drug resistance, drug pairs vary in their ability to do so. Thus, predictive models are needed to rationally design resistance-limiting therapeutic regimens. Using adaptive evolution, we studied the resistance response of the common pathogen Escherichia coli to 5 different single antibiotics and all 10 different antibiotic drug pairs. By analyzing the genomes of all evolved E. coli lineages, we identified the mutational events that drive the differences in drug resistance levels and found that the degree of resistance development against drug combinations can be understood in terms of collateral sensitivity and resistance that occurred during adaptation to the component drugs. Then, using engineered E. coli strains, we confirmed that drug resistance mutations that imposed collateral sensitivity were suppressed in a drug pair growth environment. These results provide a framework for rationally selecting drug combinations that limit resistance evolution.
Department of Systems Biology, Technical University of Denmark, DK-2800 Lyngby, Denmark.
Christian
C
Munck
Department of Systems Biology, Technical University of Denmark, DK-2800 Lyngby, Denmark.
Heidi K
HK
Gumpert
Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, DK-2970 Hørsholm, Denmark.
Annika I Nilsson
AI
Wallin
Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA.
Harris H
HH
Wang
Department of Systems Biology, Technical University of Denmark, DK-2800 Lyngby, Denmark. Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, DK-2970 Hørsholm, Denmark. msom@bio.dtu.dk.
Morten O A
MO
Sommer
D000483:Alleles; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D004252:DNA Mutational Analysis; D015195:Drug Design; D004347:Drug Interactions; D024881:Drug Resistance, Bacterial; D004359:Drug Therapy, Combination / Q000009:adverse effects*; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics*; D019143:Evolution, Molecular; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D009154:Mutation; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide
D000900:Anti-Bacterial Agents