Prediction of resistance development against drug combinations by collateral responses to component drugs

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Science Translational Medicine  12 Nov 2014:
Vol. 6, Issue 262, pp. 262ra156
DOI: 10.1126/scitranslmed.3009940

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It Takes Two—But Which Two?

Long-term treatment regimens—such as those prescribed for patients with tuberculosis or cancer—often drive development of drug resistance. Treatment with two or more drugs reduces resistance evolution, but not all drug pairs are created equally. Predictive models are needed to permit the rational design of resistance-limiting therapeutic regimens. To design such models, Munck et al. used adaptive evolution and genomic analysis to decipher the resistance response of pathogenic Escherichia coli to 5 different single antibiotics and ten different antibiotic drug pairs.

Resistance mutations often occur in key genes influencing the overall homeostasis of the cell. As a result, organisms that develop resistance to one drug sometimes display a greater sensitivity to a second drug (collateral sensitivity). The authors analyzed the genomes of evolved resistant E. coli lineages and pinpointed the mutational events that gave rise to differences in drug-resistance levels and collateral sensitivity and illuminated mechanisms that underlie the development of resistance to drug combinations. Furthermore the authors demonstrate that this effect can be exploited to design drug combinations that limit drug resistance and even select against resistance mutations. The resulting framework sets the stage for rational selection of drug combinations that limit resistance development.

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