Abstract
In wild-type Saccharomyces cerevisiae, erythromycin and certain other antibacterial antibiotics inhibit the formation of respiratory enzymes in mitochondria by inhibiting translation on mitochondrial ribosomes. This paper is concerned with the origin of mutant cells, resistant to erythromycin by virtue of having a homogeneous population of mutant mitochondrial DNA molecules. Such mutant cells are obtained by plating wild-type (sensitive) cells on a nonfermentable substrate plus the antibiotic. Colonies of mutant cells appear first about four days after the time of appearance of established mutant cells; new colonies continue to appear, often at a constant rate, for many days. Application of the Newcombe respreading experiment demonstrates that most or all of the mutant cells which form the resistant colonies on selective medium arise only after exposure of the population to erythromycin. It is suggested that this result is most probably due to intracellular selection for mitochondrial genomes. Resistant mitochondria arising from spontaneous mutation are postulated to be at a selective disadvantage in the absence of erythromycin; reproducing more slowly than wild-type sensitive mitochondria, they cannot easily accumulate in sufficient numbers in a cell to render it resistant as a whole. In the presence of erythromycin, resistant mitochondria can continue to reproduce while sensitive mitochondria cannot, until there is a sufficient number to make the cell resistant, i.e. to permit normal cell growth. The same phenomenon is seen with respect to chloramphenicol resistance. Intracellular selection is considered more likely than direct induction of mutation by the antibiotic, since mutant cells do not accumulate in the presence of erythromycin if the mitochondrial genome is rendered non-essential by growth on glucose or nontranslatable by chloramphenicol. Intra-cellular selection provides a mechanism for direct adaptation at the cell level, compatible with currently acceptable ideas of spontaneous mutation and selection at the organelle level.
Full Text
The Full Text of this article is available as a PDF (789.2 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Adoutte A., Beisson J. Cytoplasmic inheritance of erythromycin resistant mutations in Paramecium aurelia. Mol Gen Genet. 1970;108(1):70–77. doi: 10.1007/BF00343186. [DOI] [PubMed] [Google Scholar]
- Beale G. H. A note on the inheritance of erythromycin-resistance in Paramecium aurelia. Genet Res. 1969 Dec;14(3):341–342. doi: 10.1017/s0016672300002184. [DOI] [PubMed] [Google Scholar]
- Beale G. H., Knowles J. K., Tait A. Mitochondrial genetics in Paramecium. Nature. 1972 Feb 18;235(5338):396–397. doi: 10.1038/235396a0. [DOI] [PubMed] [Google Scholar]
- Bunn C. L., Mitchell C. H., Lukins H. B., Linnane A. W. Biogenesis of mitochondria. 18. A new class of cytoplasmically determined antibiotic resistant mutants in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 1970 Nov;67(3):1233–1240. doi: 10.1073/pnas.67.3.1233. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Linnane A. W., Saunders G. W., Gingold E. B., Lukins H. B. The biogenesis of mitochondria. V. Cytoplasmic inheritance of erythromycin resistance in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 1968 Mar;59(3):903–910. doi: 10.1073/pnas.59.3.903. [DOI] [PMC free article] [PubMed] [Google Scholar]
- OGUR M., ST. JOHN R., NAGAI S. Tetrazolium overlay technique for population studies of respiration deficiency in yeast. Science. 1957 May 10;125(3254):928–929. doi: 10.1126/science.125.3254.928. [DOI] [PubMed] [Google Scholar]
- Perlman P. S., Mahler H. R. Intracellular localization of enzymes in yeast. Arch Biochem Biophys. 1970 Jan;136(1):245–259. doi: 10.1016/0003-9861(70)90348-6. [DOI] [PubMed] [Google Scholar]
- SAGER R. Streptomycin as a mutagen for nonchromosomal genes. Proc Natl Acad Sci U S A. 1962 Dec 15;48:2018–2026. doi: 10.1073/pnas.48.12.2018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wickerham L. J. A Critical Evaluation of the Nitrogen Assimilation Tests Commonly Used in the Classification of Yeasts. J Bacteriol. 1946 Sep;52(3):293–301. [PMC free article] [PubMed] [Google Scholar]
- Williamson D. H., Maroudas N. G., Wilkie D. Induction of the cytoplasmic petite mutation in Saccharomyces cerevisiae by the antibacterial antibiotics erythromycin and chloramphenicol. Mol Gen Genet. 1971;111(3):209–223. doi: 10.1007/BF00433106. [DOI] [PubMed] [Google Scholar]