Universität zu Köln

Schenk, Martijn F., Witte, Sariette, Salverda, Merijn L. M., Koopmanschap, Bertha, Krug, Joachim ORCID: 0000-0002-2143-6490 and de Visser, J. Arjan G. M. (2015). Role of pleiotropy during adaptation of TEM-1 beta-lactamase to two novel antibiotics. Evol. Appl., 8 (3). S. 248 - 261. HOBOKEN: WILEY. ISSN 1752-4571

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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 -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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Schenk, Martijn F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Witte, Sariette UNSPECIFIED UNSPECIFIED UNSPECIFIED Salverda, Merijn L. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Koopmanschap, Bertha UNSPECIFIED UNSPECIFIED UNSPECIFIED Krug, Joachim UNSPECIFIED orcid.org/0000-0002-2143-6490 UNSPECIFIED de Visser, J. Arjan G. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-405811
DOI:	10.1111/eva.12200
Journal or Publication Title:	Evol. Appl.
Volume:	8
Number:	3
Page Range:	S. 248 - 261
Date:	2015
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1752-4571
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Physics > Institut für Biologische Physik
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language EMPIRICAL FITNESS LANDSCAPES; BENEFICIAL MUTATIONS; NATURAL EVOLUTION; RESISTANCE; EPISTASIS Multiple languages Evolutionary Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/40581