Directed evolution, in which natural evolution is imitated by various DNA modification techniques, can be used to model the emergence of antibiotic resistance in bacteria. Researchers at Scripps Research Institute (La Jolla, CA) and biotechnology company Maxygen (Redwood City, CA) have now shown that a combination of directed evolution and structural analysis accurately follows the evolution of β-lactam resistance in bacteria (Nat. Struct. Biol. 8, 239–242, 2001). In all instances, directed evolution of β-lactamase resulted in three specific mutations (E104K, M182T, and G238S), which were seen in the so-called TEM-52 clinical isolate of Escherichia coli. TEM-52 is more than 500-fold more resistant to the antibiotic cefotaxime than wild-type E. coli. Structural analysis revealed that two of the TEM-52 mutations widened access to the active site of β-lactamase, increasing its affinity for cefotaxime. However, the third mutation acted at a distance from the active site, stabilizing the previous structural alterations and further enhancing antibiotic resistance. Scripps' Raymond Stevens, lead author on the paper, says that the team will “look at future mutations of lactamases and other enzymes that evolve based on their response to drug treatment.” In the meantime, the “stabilizer” region of the mutant β-lactamase could be used as a target for the development of new anti-biotics.