Evolution of β-lactamases and enzyme promiscuity

β-Lactamases represent one of the most prevalent resistance mechanisms against β-lactam antibiotics. Beyond their clinical importance, they have also become key models in enzymology and evolutionary biochemistry. A global understanding of their evolution and sequence and functional diversity can therefore aid a wide set of different disciplines. Interestingly, β-lactamases have evolved multiple times from distinct evolutionary origins, with ancestries that reach back billions of years. It is therefore no surprise that these enzymes exhibit diverse structural features and enzymatic mechanisms. In this review, we provide a bird's eye view on the evolution of β-lactamases within the two enzyme superfamilies-i.e. the penicillin-binding protein-like and metallo-β-lactamase superfamily-through phylogenetics. We further discuss potential evolutionary origins of each β-lactamase class by highlighting signs of evolutionary connections in protein functions between β-lactamases and other enzymes, especially cases of enzyme promiscuity.