Role of Synonymous Mutations in the Evolution of TEM β-Lactamase Genes
| Autor: | Juergen Pleiss, Peter Oelschlaeger, Charles J Zhang, Mohammad Faheem, Monica N Morris |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Silent mutation
Nonsynonymous substitution Microbial Sensitivity Tests Biology medicine.disease_cause beta-Lactamases 03 medical and health sciences 0302 clinical medicine Mechanisms of Resistance medicine Escherichia coli Missense mutation Humans Pharmacology (medical) Gene Escherichia coli Infections Silent Mutation 030304 developmental biology Pharmacology Genetics 0303 health sciences Transition (genetics) Phenotype Infectious Diseases 030220 oncology & carcinogenesis Synonymous substitution |
| Zdroj: | Antimicrob Agents Chemother |
| ISSN: | 1098-6596 |
| Popis: | Nonsynonymous mutations are well documented in TEM β-lactamases. The resulting amino acid changes often alter the conferred phenotype from broad spectrum (2b) conferred by TEM-1 to extended spectrum (2be), inhibitor resistant (2br), or both extended spectrum and inhibitor resistant (2ber). The encoding bla(TEM) genes also deviate in numerous synonymous mutations, which are not well understood. bla(TEM-3) (2be), bla(TEM-33) (2br), and bla(TEM-109) (2ber) were studied in comparison to bla(TEM-1). bla(TEM-33) was chosen for more detailed studies because it deviates from bla(TEM-1) by a single nonsynonymous mutation and three additional synonymous mutations. Genes encoding the enzymes with only nonsynonymous or all (including synonymous) mutations plus all permutations between bla(TEM-1) and bla(TEM-33) were expressed in Escherichia coli cells. In disc diffusion assays, genes encoding TEM-3, TEM-33, and TEM-109 with all synonymous mutations resulted in higher resistance levels than genes without synonymous mutations. Disc diffusion assays with the 16 genes carrying all possible nucleotide change combinations between bla(TEM-1) and bla(TEM-33) indicated different susceptibilities for different variants. Nucleotide BLAST searches did not identify genes without synonymous mutations but did identify some without nonsynonymous mutations. Energies of possible secondary mRNA structures calculated with mfold are generally higher with synonymous mutations, suggesting that their role could be to destabilize the mRNA and facilitate its unfolding for efficient translation. In summary, our data indicate that transition from bla(TEM-1) to other variant genes by simply acquiring the nonsynonymous mutations is not favored. Instead, synonymous mutations seem to support the transition to other variant genes with nonsynonymous mutations leading to different phenotypes. |
| Databáze: | OpenAIRE |
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