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Unfortunately, the efficacy of these life-saving antibiotics is significantly threatened by bacterial \u03b2-lactamases. \u03b2-Lactamases are now responsible for resistance to penicillins, extended-spectrum cephalosporins, monobactams, and carbapenems. In order to overcome \u03b2-lactamase-mediated resistance, \u03b2-lactamase inhibitors (clavulanate, sulbactam, and tazobactam) were introduced into clinical practice. These inhibitors greatly enhance the efficacy of their partner \u03b2-lactams (amoxicillin, ampicillin, piperacillin, and ticarcillin) in the treatment of serious<jats:italic>Enterobacteriaceae<\/jats:italic>and penicillin-resistant staphylococcal infections. However, selective pressure from excess antibiotic use accelerated the emergence of resistance to \u03b2-lactam-\u03b2-lactamase inhibitor combinations. Furthermore, the prevalence of clinically relevant \u03b2-lactamases from other classes that are resistant to inhibition is rapidly increasing. There is an urgent need for effective inhibitors that can restore the activity of \u03b2-lactams. Here, we review the catalytic mechanisms of each \u03b2-lactamase class. We then discuss approaches for circumventing \u03b2-lactamase-mediated resistance, including properties and characteristics of mechanism-based inactivators. We next highlight the mechanisms of action and salient clinical and microbiological features of \u03b2-lactamase inhibitors. We also emphasize their therapeutic applications. We close by focusing on novel compounds and the chemical features of these agents that may contribute to a \u201csecond generation\u201d of inhibitors. The goal for the next 3 decades will be to design inhibitors that will be effective for more than a single class of \u03b2-lactamases.<\/jats:p><\/jats:sec>","DOI":"10.1128\/cmr.00037-09","type":"journal-article","created":{"date-parts":[[2010,1,12]],"date-time":"2010-01-12T00:22:47Z","timestamp":1263255767000},"page":"160-201","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1532,"title":["Three Decades of \u03b2-Lactamase Inhibitors"],"prefix":"10.1128","volume":"23","author":[{"given":"Sarah M.","family":"Drawz","sequence":"first","affiliation":[{"name":"Departments of Pathology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Bonomo","sequence":"additional","affiliation":[{"name":"Medicine"},{"name":"Pharmacology"},{"name":"Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio"},{"name":"Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","first-page":"837","volume":"146","year":"1940","unstructured":"Abraham, E. 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