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 language | English (US) |
|---|---|
| Pages (from-to) | 1183-1195 |
| Number of pages | 13 |
| Journal | Genetics |
| Volume | 182 |
| Issue number | 4 |
| DOIs | |
| State | Published - Aug 2009 |
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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 journal › Article
}
TY - JOUR
T1 - Contribution of gene amplification to evolution of increased antibiotic resistance in Salmonella typhimurium
AU - Song, Sun
AU - Berg, Otto G.
AU - Roth, John R.
AU - Andersson, Dan I.
PY - 2009/8
Y1 - 2009/8
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=70350173307&partnerID=8YFLogxK
U2 - 10.1534/genetics.109.103028
DO - 10.1534/genetics.109.103028
M3 - Article
C2 - 19474201
AN - SCOPUS:70350173307
VL - 182
SP - 1183
EP - 1195
JO - Genetics
JF - Genetics
SN - 0016-6731
IS - 4
ER -