Originally published as Genetics Published Articles Ahead of Print on May 27, 2009.

Genetics, Vol. 182, 1183-1195, August 2009, Copyright © 2009
doi:10.1534/genetics.109.103028

Contribution of Gene Amplification to Evolution of Increased Antibiotic Resistance in Salmonella typhimurium

Song Sun^*, Otto G. Berg, John R. Roth and Dan I. Andersson^*,1

^* Department of Medical Biochemistry and Microbiology, Uppsala University, S-75123 Uppsala, Sweden, Department of Molecular Evolution, Uppsala University, S-75236 Uppsala, Sweden and Department of Microbiology, College of Biological Sciences, University of California, Davis, California 95616

¹ Corresponding author: Department of Medical Biochemistry and Microbiology, Uppsala University, S-75123 Uppsala, Sweden.
E-mail: dan.andersson{at}imbim.uu.se

The use of β-lactam antibiotics has led to the evolution and global spread of a variety of resistance mechanisms, including β-lactamases, a group of enzymes that degrade the β-lactam ring. The evolution of increased β-lactam resistance was studied by exposing independent lineages of Salmonella typhimurium to progressive increases in cephalosporin concentration. Each lineage carried a β-lactamase gene (bla_TEM-1) that provided very low resistance. In most lineages, the initial response to selection was an amplification of the bla_TEM-1 gene copy number. Amplification was followed in some lineages by mutations (envZ, cpxA, or nmpC) that reduced expression of the uptake functions, the OmpC, OmpD, and OmpF porins. The initial resistance provided by bla_TEM-1 amplification allowed the population to expand sufficiently to realize rare secondary point mutations. Mathematical modeling showed that amplification often is likely to be the initial response because events that duplicate or further amplify a gene are much more frequent than point mutations. These models show the importance of the population size to appearance of later point mutations. Transient gene amplification is likely to be a common initial mechanism and an intermediate in stable adaptive improvement. If later point mutations (allowed by amplification) provide sufficient adaptive improvement, the amplification may be lost.

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Online ISSN: 1943-2361  Print ISSN: 0016-6731
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