Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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Record number 495181
Title Role of pleiotropy during adaptation of TEM-1 β-lactamase to two novel antibiotics
Author(s) Schenk, M.F.; Witte, Sariette; Salverda, M.L.M.; Koopmanschap, Bertha; Krug, Joachim; Visser, J.A.G.M. de
Source Evolutionary Applications 8 (2015)3. - ISSN 1752-4563 - p. 248 - 260.
DOI https://doi.org/10.1111/eva.12200
Department(s) Laboratory of Genetics
PE&RC
Publication type Refereed Article in a scientific journal
Publication year 2015
Keyword(s) Antibiotic resistance - Epistasis - Pleiotropy - Protein evolution - TEM-1 β-lactamase - Trade-off
Abstract

Pleiotropy is a key feature of the genotype-phenotype map, and its form and extent have many evolutionary implications, including for the dynamics of adaptation and the evolution of specialization. Similarly, pleiotropic effects of antibiotic resistance mutations may affect the evolution of antibiotic resistance in the simultaneous or fluctuating presence of different antibiotics. Here, we study the role of pleiotropy during the in vitro adaptation of the enzyme TEM-1 β-lactamase to two novel antibiotics, cefotaxime (CTX) and ceftazidime (CAZ). We subject replicate lines for four rounds of evolution to selection with CTX and CAZ alone, and in their combined and fluctuating presence. Evolved alleles show positive correlated responses when selecting with single antibiotics. Nevertheless, pleiotropic constraints are apparent from the effects of single mutations and from selected alleles showing smaller correlated than direct responses and smaller responses after simultaneous and fluctuating selection with both than with single antibiotics. We speculate that these constraints result from structural changes in the oxyanion pocket surrounding the active site, where accommodation of CTX and the larger CAZ is balanced against their positioning with respect to the active site. Our findings suggest limited benefits from the combined or fluctuating application of these related cephalosporins for containing antibiotic resistance.

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