Epidemiological Expansion, Structural Studies, and Clinical Challenges of New beta-Lactamases from Gram-Negative Bacteria

beta-Lactamase evolution presents to the infectious disease community a major challenge in the treatment of infections caused by multidrug-resistant gram-negative bacteria. Because over 1,000 of these naturally occurring beta-lactamases exist, attempts to correlate structure and function have become daunting. Although new enzymes in the extended-spectrum beta-lactamase (ESBL) families are frequently identified, the older CTX-M-14 and CTX-M-15 enzymes have become the most prevalent ESBLs in global surveillance. Carbapenemases with either serine-based or zinc-facilitated hydrolysis mechanisms are posing some of the most critical problems. Most geographical regions now report KPC serine carbapenemases and the metallo-beta-lactamases VIM, IMP, and NDM-1, even though NDM-1 was only recently identified. The rapid emergence of these newer enzymes, with multiple beta-lactamases appearing in a single organism, makes the design of new beta-lactamase inactivators or beta-lactamase-stable beta-lactams all the more difficult. Combination therapy will likely be required to counteract the continuing evolution of these insidious enzymes in multidrug-resistant pathogens.