Research ArticleAntibiotics

Use of Collateral Sensitivity Networks to Design Drug Cycling Protocols That Avoid Resistance Development

Science Translational Medicine  25 Sep 2013:
Vol. 5, Issue 204, pp. 204ra132
DOI: 10.1126/scitranslmed.3006609

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Resistance is Futile

In an emergency situation, people are often instructed to remain calm and proceed in an orderly fashion. The same advice may apply to the current antibiotic-resistance crisis. Imamovic and Sommer now show how collateral sensitivity profiles—deciphered by treating bacteria with multiple antibiotics—can help to order drug deployment in sequences that thwart the development of antibiotic resistance.

Cells or organisms that have developed resistance to one drug sometimes display a greater sensitivity to a second drug often from a distinct structural class, a concept called collateral sensitivity. The authors tested whether application of this concept can aid in the management of bacterial infections by evolving resistance in Escherichia coli to 23 known antibiotics and then mapping the resulting collateral sensitivity and resistance profiles. On the basis of their derived collateral sensitivity network, the authors designed a new treatment framework—collateral sensitivity cycling—in which sequential treatment of E. coli cultures with antibiotics that display compatible collateral sensitivity profiles is predicted to select against drug-resistance development. The authors chronicled hundreds of such drug sets and validated their predictions E. coli and the antibiotics gentamicin and cefuroxime by showing that cyclical deployment of the drugs selected against resistance to either antibiotic. This proof of principle for collateral sensitivity cycling as a sustainable treatment regimen was then validated with two related bacterial pathogens. It remains to be seen whether deployment of cancer therapeutics in an orderly fashion also curbs drug resistance.