Let's Dance: How Protein Dynamics Drive β-Lactamase Evolution and Antibiotic Resistance?

β-Lactamases are the major mechanism of antimicrobial resistance to β-lactam antibiotics in Gram-negative bacteria. Continuous exposure to these drugs has resulted in >12,400 known variants due to evolutionary pressure. These enzymes represent a unique model for studying protein evolution, as bacterial survival depends on expressing β-lactamases that inactivate the specific β-lactam antibiotic that the bacterium encounters. In this perspective, we discuss salient examples in which changes in protein dynamics have played a role in the evolution of β-lactamases. Our analysis is based in the concept that proteins explore alternative conformations, and mutations can favor some of these conformations, providing a "gain-of-function" to the enzyme. The role of less-populated conformations and cryptic binding sites in evolution is discussed, as well as state-of-the-art experimental approaches that can study the role of alternative conformations in evolution. This approach also reveals opportunities to develop allosteric inhibitors that take advantage of these alternative conformations.