Collateral sensitivity and the evolution of drug resistance in Escherichia coli

Abstract

Recently, collateral sensitivity networks have created excitement for designing new therapies that could reduce rates of evolution of antibiotic resistance in pathogens. To explore this idea, I tested the key assumption that collateral sensitivity should reduce the frequency of mutation to resistance. Thirty strains of Escherichia coli, each selected for resistance to a single antibiotic, were screened for minimum inhibitory concentration values against twelve drugs to find relationships of collateral sensitivity. Ceftazidime resistant strains showed susceptibility to chloramphenicol. It was therefore expected that growth in sub-MIC concentrations of chloramphenicol would reduce mutation rate to ceftazidime resistance, however, an increase in mutation rate was observed. The results showed that µ was significantly higher in populations evolved in sub-MIC concentrations of cef, compared to plain LB (p = 2.93x10 -5 ) For populations grown in LB µ was 0.011 per 10 9 cells, 95% CI [0.019, 0.005] whereas populations grown in LB and sub-MIC cef, µ was 0.21 per 10 9 cells, 95% CI [0.452,0.158]. There are two likely hypotheses, the first is that the increase in mutation is due to antibiotic related SOS response, and the second is that multi-drug-resistance was selected for in both cases. This highlights the need for evolutionary considerations in designing new drug therapies, as apparent patterns of collateral sensitivity may not be a sufficient criterion.iii AcknowledgementsIt is my belief that the Scientist is the most noble of all God's creatures. To be clear, I do not mean God in a strict religious sense but to signify, as Immanuel Kant did for his age, that science and religion are not so different. They both require a kind of faith enshrined in their devoted. I further believe that anyone who tells you otherwise is lying, or trying to sell you something. In the latter case, the false idea that the practice of Science can offer us any control over nature. This idea is a lie, yet somehow it is true.We live longer, better, and with more opportunity as a species today than ever before, solely because of Scientists. However, do not let the general scientific institution impress you, for not all scientists are Scientists. Therefore, I say that the Scientist is the most noble creature. For a lifetime, the Scientist endures the very human task of drowning in their own mortality as it makes liars of us all, but more than others, they flail in a desperate search for elusive Truths as they bob between the waves. The Scientist bears it all in good faith that their contributions will, one day -through a kind of prayer -bear fruits for those they will never meet. It is a kind of selflessness we cannot expect from evolutionary theory, and thus it is perhaps the least scientific way of life, thus making Scientists the least scientific creatures, and so the most noble. For there is nothing noble in the calculation of humanity, only the arduous Truth behind it. Our greatest achievements as a species come soundly from this self-denyin...