beta-Lactamases of gram-negative bacteria: new challenges for new drugs.
The major emphasis in new drug design within the beta-lactam family has been on compounds less susceptible to hydrolysis by beta-lactamases and on combinations containing an enzyme-labile drug plus a beta-lactamase inhibitor. The introduction of such new compounds into clinical use has been followed by the discovery of novel mechanisms of resistance among gram-negative bacteria. These include the appearance of new enzymes, many of which are derivatives of older beta-lactamases. In addition, genes for certain broad-spectrum enzymes previously restricted to chromosomal sites have moved onto plasmids. There is now a greater appreciation of how alterations in enzyme expression--either alone or in concert with changes in drug permeation--can also lead to resistance. Clearly, recent events in the development of new beta-lactam agents have led to a new phase in the understanding of beta-lactam resistance.
Sanders
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Department of Medical Microbiology, Creighton University School of Medicine, Omaha, Nebraska 68178.
D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000494:pharmacology; D015195:Drug Design; D004352:Drug Resistance, Microbial / Q000235:genetics / Q000502:physiology; D015964:Gene Expression Regulation, Bacterial; D015971:Gene Expression Regulation, Enzymologic; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000201:enzymology*; D001618:beta-Lactamases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D047090:beta-Lactams
D000900:Anti-Bacterial Agents; D047090:beta-Lactams; D001618:beta-Lactamases