Contribution of gene amplification to evolution of increased antibiotic resistance in Salmonella typhimurium

Sun Song, Otto G. Berg, John R. Roth, Dan I. Andersson

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

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 (blaTEM-1) that provided very low resistance. In most lineages, the initial response to selection was an amplification of the blaTEM-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 blaTEM-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.

Original languageEnglish (US)
Pages (from-to)1183-1195
Number of pages13
JournalGenetics
Volume182
Issue number4
DOIs
StatePublished - Aug 2009

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Gene Amplification
Salmonella typhimurium
Microbial Drug Resistance
Point Mutation
Lactams
Porins
Gene Dosage
Cephalosporins
Population Density
Genes
Anti-Bacterial Agents
Mutation
Enzymes
Population

ASJC Scopus subject areas

  • Genetics

Cite this

Contribution of gene amplification to evolution of increased antibiotic resistance in Salmonella typhimurium. / Song, Sun; Berg, Otto G.; Roth, John R.; Andersson, Dan I.

In: Genetics, Vol. 182, No. 4, 08.2009, p. 1183-1195.

Research output: Contribution to journalArticle

Song, Sun ; Berg, Otto G. ; Roth, John R. ; Andersson, Dan I. / Contribution of gene amplification to evolution of increased antibiotic resistance in Salmonella typhimurium. In: Genetics. 2009 ; Vol. 182, No. 4. pp. 1183-1195.
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