Department of Medical Biochemistry and Microbiology, Uppsala University, S-75123, Sweden.
Genetics. 2009 Aug;182(4):1183-95. doi: 10.1534/genetics.109.103028. Epub 2009 May 27.
The use of beta-lactam antibiotics has led to the evolution and global spread of a variety of resistance mechanisms, including beta-lactamases, a group of enzymes that degrade the beta-lactam ring. The evolution of increased beta-lactam resistance was studied by exposing independent lineages of Salmonella typhimurium to progressive increases in cephalosporin concentration. Each lineage carried a beta-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.
β-内酰胺类抗生素的使用导致了各种耐药机制的进化和全球传播，包括β-内酰胺酶，这是一组能够降解β-内酰胺环的酶。通过将鼠伤寒沙门氏菌的独立谱系暴露于头孢菌素浓度的逐渐增加，研究了增加的β-内酰胺耐药性的进化。每个谱系都携带一种β-内酰胺酶基因（bla(TEM-1)），该基因提供了非常低的耐药性。在大多数谱系中，对选择的最初反应是 bla(TEM-1)基因拷贝数的扩增。在一些谱系中，扩增后会发生突变（envZ、cpxA 或 nmpC），从而降低摄取功能、OmpC、OmpD 和 OmpF 孔蛋白的表达。bla(TEM-1)扩增提供的初始耐药性使种群得以充分扩张，从而实现罕见的二次点突变。数学模型表明，扩增通常很可能是最初的反应，因为复制或进一步扩增基因的事件比点突变要频繁得多。这些模型表明了种群大小对后期点突变出现的重要性。短暂的基因扩增可能是一种常见的初始机制，也是稳定适应性改善的中间过程。如果后期的点突变（由扩增所允许）提供了足够的适应性改善，那么扩增可能会丢失。
