Role of pleiotropy during adaptation of TEM‐1 β‐lactamase to two novel antibiotics

Evolutionary Applications

Martijn F. Schenk³  Sariette Witte²  Merijn L. M. Salverda²  Bertha Koopmanschap²  Joachim Krug¹ 

[1] Institute for Theoretical Physics, University of Cologne, Köln, Germany;Laboratory of Genetics, Wageningen University, Wageningen, The Netherlands;Institute of Genetics, University of Cologne, Köln, Germany

关键词: antibiotic resistance;    epistasis;    pleiotropy;    protein evolution;    TEM‐1 β‐lactamase;    trade‐off;   

DOI  :  10.1111/eva.12200

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2014 The Authors. Evolutionary Applications published by John Wiley & Sons Ltd.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.