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

• Published in: Annual review of microbiology 2011-01, Vol.65 (1), p.455-478
• Main Authors: Bush, Karen, Fisher, Jed F
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - chemistry; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; beta -Lactam antibiotics; beta -Lactamase; beta-Lactamase Inhibitors; beta-Lactamases - chemistry; beta-Lactamases - genetics; beta-Lactamases - metabolism; carbapenemase; cephalosporin; cephalosporinase; Drug resistance; Drug Resistance, Multiple, Bacterial; Enzyme Inhibitors - pharmacology; Enzymes; Evolution; Gram-negative bacteria; Gram-Negative Bacteria - chemistry; Gram-Negative Bacteria - drug effects; Gram-Negative Bacteria - enzymology; Gram-Negative Bacteria - genetics; Gram-Negative Bacterial Infections - drug therapy; Gram-Negative Bacterial Infections - epidemiology; Gram-Negative Bacterial Infections - microbiology; Humans; Hydrolysis; Inactivators; Infection; Infectious diseases; Inosine monophosphate; Metallo- beta -lactamase; Pathogens; resistance; Reviews; Serine; Structure-function relationships; β-lactam
• ISSN: 0066-4227; 1545-3251
• DOI: 10.1146/annurev-micro-090110-102911

β-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 β-lactamases exist, attempts to correlate structure and function have become daunting. Although new enzymes in the extended-spectrum β-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-β-lactamases VIM, IMP, and NDM-1, even though NDM-1 was only recently identified. The rapid emergence of these newer enzymes, with multiple β-lactamases appearing in a single organism, makes the design of new β-lactamase inactivators or β-lactamase-stable β-lactams all the more difficult. Combination therapy will likely be required to counteract the continuing evolution of these insidious enzymes in multidrug-resistant pathogens.