RT Journal Article
SR Electronic
T1 Prediction of resistance development against drug combinations by collateral responses to component drugs
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP 262ra156
OP 262ra156
DO 10.1126/scitranslmed.3009940
VO 6
IS 262
A1 Munck, Christian
A1 Gumpert, Heidi K.
A1 Wallin, Annika I. Nilsson
A1 Wang, Harris H.
A1 Sommer, Morten O. A.
YR 2014
UL http://stm.sciencemag.org/content/6/262/262ra156.abstract
AB 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.