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      Alternative Evolutionary Paths to Bacterial Antibiotic Resistance Cause Distinct Collateral Effects

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          Abstract

          When bacteria evolve resistance against a particular antibiotic, they may simultaneously gain increased sensitivity against a second one. Such collateral sensitivity may be exploited to develop novel, sustainable antibiotic treatment strategies aimed at containing the current, dramatic spread of drug resistance. To date, the presence and molecular basis of collateral sensitivity has only been studied in few bacterial species and is unknown for opportunistic human pathogens such as Pseudomonas aeruginosa. In the present study, we assessed patterns of collateral effects by experimentally evolving 160 independent populations of P. aeruginosa to high levels of resistance against eight commonly used antibiotics. The bacteria evolved resistance rapidly and expressed both collateral sensitivity and cross-resistance. The pattern of such collateral effects differed to those previously reported for other bacterial species, suggesting interspecific differences in the underlying evolutionary trade-offs. Intriguingly, we also identified contrasting patterns of collateral sensitivity and cross-resistance among the replicate populations adapted to the same drug. Whole-genome sequencing of 81 independently evolved populations revealed distinct evolutionary paths of resistance to the selective drug, which determined whether bacteria became cross-resistant or collaterally sensitive towards others. Based on genomic and functional genetic analysis, we demonstrate that collateral sensitivity can result from resistance mutations in regulatory genes such as nalC or mexZ, which mediate aminoglycoside sensitivity in β-lactam-adapted populations, or the two-component regulatory system gene pmrB, which enhances penicillin sensitivity in gentamicin-resistant populations. Our findings highlight substantial variation in the evolved collateral effects among replicates, which in turn determine their potential in antibiotic therapy.

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          Most cited references60

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          Long-Term Experimental Evolution in Escherichia coli. I. Adaptation and Divergence During 2,000 Generations

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            Multidrug-resistance efflux pumps - not just for resistance.

            It is well established that multidrug-resistance efflux pumps encoded by bacteria can confer clinically relevant resistance to antibiotics. It is now understood that these efflux pumps also have a physiological role(s). They can confer resistance to natural substances produced by the host, including bile, hormones and host-defence molecules. In addition, some efflux pumps of the resistance nodulation division (RND) family have been shown to have a role in the colonization and the persistence of bacteria in the host. Here, I present the accumulating evidence that multidrug-resistance efflux pumps have roles in bacterial pathogenicity and propose that these pumps therefore have greater clinical relevance than is usually attributed to them.
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              Pseudomonas aeruginosa: all roads lead to resistance.

              Pseudomonas aeruginosa is often resistant to multiple antibiotics and consequently has joined the ranks of 'superbugs' due to its enormous capacity to engender resistance. It demonstrates decreased susceptibility to most antibiotics due to low outer membrane permeability coupled to adaptive mechanisms and can readily achieve clinical resistance. Newer research, using mutant library screens, microarray technologies and mutation frequency analysis, has identified very large collections of genes (the resistome) that when mutated lead to resistance as well as new forms of adaptive resistance that can be triggered by antibiotics themselves, in in vivo growth conditions or complex adaptations such as biofilm growth or swarming motility. Copyright © 2011 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Mol Biol Evol
                Mol. Biol. Evol
                molbev
                Molecular Biology and Evolution
                Oxford University Press
                0737-4038
                1537-1719
                September 2017
                23 May 2017
                23 May 2017
                : 34
                : 9
                : 2229-2244
                Affiliations
                [1 ]Evolutionary Ecology and Genetics, Zoological Institute, CAU Kiel, Kiel, Germany
                [2 ]BioVersys AG, Basel, Switzerland
                [3 ]Institute of Clinical Molecular Biology (IKMB), CAU Kiel, Kiel, Germany
                [4 ]Biosciences, University of Exeter, Exeter, United Kingdom
                Author notes

                Associate editor: Csaba Pal

                Article
                msx158
                10.1093/molbev/msx158
                5850482
                28541480
                2312a71d-79e3-4d9c-b2f0-3b13a2ed9dd7
                © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                Page count
                Pages: 16
                Categories
                Discoveries

                Molecular biology
                antibiotic resistance,pseudomonas aeruginosa,experimental evolution,trade-offs,collateral sensitivity

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