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J Mol Evol (1990) 30:489-492 Journal of Molecular Evolution (~) Springer-Vcrlag New York Inc. 1990 Evolutionary Origin of Aminoglycoside Phosphotransferase Resistance Genes Ralph Kirby Department of Microbiology, Rhodes University, P.O. Box 94, Graham's Town 6140, Republic of South Africa Summary. The protein sequences of seven 3'-ami- noglycoside phosphotransferases falling into the six identified types and three 6'-aminoglycoside phos- photransferases were analyzed to give a rooted phy- logenetic tree. This tree supports the origin of these groups of enzymes in an ancestor closely related to the actinomycetes, and that horizontal transfer of the resistance genes occurred, possibly via transpo- sons. The implications for genetic engineering of a novel antibiotic are discussed. Key words: Actinomyces -- Phosphotransferase -- Aminoglycoside -- Phylogenetic tree -- Evolu- tion Introduction The resistance to aminoglycoside antibiotics is widespread throughout prokaryotes. Resistance is mainly the result of production of enzymes that modify the antibiotics. There are three classes of such enzymes in turn named according to the site that they modify on the antibiotic: phosphotrans- ferases, acetyl transferases, and nucleotidyltransfer- ases. The most common aminoglycoside-modifying enzymes in prokaryotes are phosphotransferases, which can be divided into the 3'-phosphotransfer- ases and the 6'-phosphotransferases. Six types (I- VI) of 3'-phosphotransferases have been identified to date. Types I, II, III, and VI are detected in human clinical isolates, whereas types IV and V are found in aminoglycoside-producing microorganisms (Brenner 1987). Three 6'-phosphotransferases have Offprint requests to: R. Kirby been sequenced, one from Escherichia coli and two from Streptomyces. The appearance of clinical aminoglycoside resis- tance has led to speculation as to the origin of this antibiotic resistance. It has been postulated that be- cause of the widespread nature of aminoglycoside production among soil organisms and the Actino- mycetales in particular, that these organisms rep- resent the original pool from which aminoglycoside resistance disseminated by horizontal transmission (Walker and Walker 1970; Benveniste and Davies 1973; Trieu-Cuot and Courvalin 1986, 1987). The possibility of independent derivation seems unlikely when the high degree of similarity between ami- noglycoside phosphotransferase resistance genes from diverse organisms is considered. Descent from a common ancestor would require that the phylog- eny of the aminoglycoside phosphotransferases match that found by Woese (1987) for 16S RNA. Although there are barriers in both DNA transfer and gene expression between actinomycetes and other organisms, the horizontal transmission hy- pothesis bears consideration because of the diverse nature of soil and the potential for selection for transfer of antibiotic resistance in the presence of antibiotic production. Two distinct methods of comparison of either DNA or protein sequence data for the production ofphylogenetic trees are available; either percentage homology of the whole genes after alignment and pairwise comparison can be used, or the aligned genes can be directly compared using every site as a determinate. The former has the advantage that it is much quicker and requires only a limited num- ber of trees to be analyzed, whereas the latter is much slower but takes into account each residue as a potential evolutionary site. It also includes inser-