The Mathematical Institute, University of Oxford, Eprints Archive

Steering evolution with sequential therapy to prevent the emergence of bacterial antibiotic resistance

Nichol, D and Jeavons, P and Fletcher, A G and Bonomo, R A and Maini, P. K. and Paul, J L and Gatenby, R. A. and Anderson, A R A and Scott, J G (2015) Steering evolution with sequential therapy to prevent the emergence of bacterial antibiotic resistance. PLOS Computational Biology, e10044 . 19 pages.

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Abstract

The increasing rate of antibiotic resistance and slowing discovery of novel antibiotic treatments presents a growing threat to public health. Here, we consider a simple model of evolution in asexually reproducing populations which considers adaptation as a biased random walk on a fitness landscape. This model associates the global properties of the fitness landscape with the algebraic properties of a Markov chain transition matrix and allows us to derive general results on the non-commutativity and irreversibility of natural selection as well as antibiotic cycling strategies. Using this formalism, we analyze 15 empirical fitness landscapes of E. coli under selection by different β-lactam antibiotics and demonstrate that the emergence of resistance to a given antibiotic can be either hindered or promoted by different sequences of drug application. Specifically, we demonstrate that the majority, approximately 70%, of sequential drug treatments with 2–4 drugs promote resistance to the final antibiotic. Further, we derive optimal drug application sequences with which we can probabilistically ‘steer’ the population through genotype space to avoid the emergence of resistance. This suggests a new strategy in the war against antibiotic–resistant organisms: drug sequencing to shepherd evolution through genotype space to states from which resistance cannot emerge and by which to maximize the chance of successful therapy.

Item Type:Article
Subjects:A - C > Biology and other natural sciences
Research Groups:Centre for Mathematical Biology
ID Code:1907
Deposited By: Philip Maini
Deposited On:10 Oct 2015 08:12
Last Modified:10 Oct 2015 08:12

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