Open AccessExperimental Prediction of the Natural Evolution of Antibiotic Resistance
Author(s) -
Miriam Barlow,
Barry G. Hall
Publication year - 2003
Publication title -
genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.792
H-Index - 246
eISSN - 1943-2631
pISSN - 0016-6731
DOI - 10.1093/genetics/163.4.1237
Subject(s) - cefepime , allele , biology , genetics , mutagenesis , antibiotics , genotype , antibiotic resistance , mutation , gene , imipenem
The TEM family of beta-lactamases has evolved to confer resistance to most of the beta-lactam antibiotics, but not to cefepime. To determine whether the TEM beta-lactamases have the potential to evolve cefepime resistance, we evolved the ancestral TEM allele, TEM-1, in vitro and selected for cefepime resistance. After four rounds of mutagenesis and selection for increased cefepime resistance each of eight independent populations reached a level equivalent to clinical resistance. All eight evolved alleles increased the level of cefepime resistance by a factor of at least 32, and the best allele improved by a factor of 512. Sequencing showed that alleles contained from two to six amino acid substitutions, many of which were shared among alleles, and that the best allele contained only three substitutions.