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J Mol Evol (1992) 34:345-350 Journal of Molecular Evolution @ Springer-Verlag New York Inc. 1992 Evolutionary Origin of the Class A and Class C/%Lactamases Ralph Kirby Department of Biochemistry and Microbiology, Rhodes University, PO Box 94, Graham's Town, Republic of South Africa Summary. The protein sequences of 18 class A 13-1actamases and 2 class C/3-1actamases were ana- lyzed to produce a rooted phylogenetic tree using the DD peptidase of Streptomyces R61 as an out- group. This tree supports the penicillin-binding pro- teins as the most likely candidate for the ancestoral origin of the class A and class C ~-lactamases, these proteins diverging from a common evolutionary or- igin close to the DD peptidase. The actinomycetes are clearly shown as the origin of the class A ~-lac- tamases found in other non-actinomycete spe- cies. The tree also divides the ~-lactamases from the Streptomyces into two subgroups. One subgroup is closer to the DD peptidase root. The other Strep- tomyces subgroup shares a common branch point with the rest of the class A/3-1actamases, showing this subgroup as the origin of the non-actinomycete class A ~3-1actamases. The non-actinomycete class A/3-1actamase phylogenetic tree suggests a spread of these /3-1actamases by horizontal transfer from the Streptomyces into the non-actinomycete gram- positive bacteria and thence into the gram-negative bacteria. The phylogenetic tree of the Streptomyces class A ~3-1actamases supports the possibility that horizontal transfer of class A (3-1actamases occurred within the Streptomyces. Key words: Evolution -- (3-Lactamase -- Phylo- genetic tree -- Horizontal transfer Introduction The presence of resistance to the 13-1actam antibi- otics in many species of bacteria is due to the wide spread of genes encoding ¢Mactamases. Much of this spread has probably been caused by the horizontal transfer of the genes for/3-1actamases under selection due to the use of 13-1actam antibiotics in hospitals. However, the evolutionary origin of the ~3-1acta- mases as resistance mechanisms against /3-1actam antibiotics is not clear especially as the use of this group of antibiotics is limited to only about 50 years. It has been postulated that the origin of the genes that can hydrolyze the/3-1actam bond lies with the penicillin-sensitive D-alanyl-D-alanine peptidase (DD peptidase), which is involved in the synthesis of peptidoglycan and is the target for/3-1actam an- tibiotics. This gene could have evolved into the 13-1actamases (Kelly et al. 1986). Huletsky et al. (1990) have made significant progress toward an- swering the question of how the class A/3-1actamases have evolved by studying the phylogeny of the SHV-2 ¢Mactamase. This study splits the class A ~-lactamases into gram-positive and gram-negative subgroups but fails to address the problem of evo- lutionary origin of the group of enzymes. In the natural environment, the major source of organisms producing antibiotics, including the 13-1actam antibiotics, is the soil. Within the soil, the actinomycetes and the Fungi are the main organisms that synthesize /3-1actam antibiotics. Phylogenetic analysis suggests that the fl-lactam production path- way of Fungi is a relatively recent addition to their genome by horizontal transfer from the actinomy- cetes (Miller and Ingolia 1989). Thus, the actino- mycetes within the soil would seem central to the production of/3-1actam antibiotics, and they can be suggested as the origin for the DD peptidase, which evolved into the/3-1actamases. This would also sug- gest that the actinomycete ~-lactamases could also be the origin from which the (3-1actamases have spread into other bacteria. In the case of aminoglycoside resistance, it has been postulated that the actinomycetes also repre-