Three Decades of β-Lactamase Inhibitors

Abstract

SUMMARYSince the introduction of penicillin, β-lactam antibiotics have been the antimicrobial agents of choice. Unfortunately, the efficacy of these life-saving antibiotics is significantly threatened by bacterial β-lactamases. β-Lactamases are now responsible for resistance to penicillins, extended-spectrum cephalosporins, monobactams, and carbapenems. In order to overcome β-lactamase-mediated resistance, β-lactamase inhibitors (clavulanate, sulbactam, and tazobactam) were introduced into clinical practice. These inhibitors greatly enhance the efficacy of their partner β-lactams (amoxicillin, ampicillin, piperacillin, and ticarcillin) in the treatment of seriousEnterobacteriaceaeand penicillin-resistant staphylococcal infections. However, selective pressure from excess antibiotic use accelerated the emergence of resistance to β-lactam-β-lactamase inhibitor combinations. Furthermore, the prevalence of clinically relevant β-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 β-lactams. Here, we review the catalytic mechanisms of each β-lactamase class. We then discuss approaches for circumventing β-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 β-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 “second generation” 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 β-lactamases.

Targeting Antibiotic Resistance

“…The third and most common mechanism of resistance is the production of β‐lactam‐hydrolyzing enzymes. These enzymes are structurally very similar to the transpeptidase enzymes and mechanistically function in a similar manner by opening the β‐lactam ring (Figure 28, orange cycle) 140. What differentiates the two is the fact that while acyl transpeptidases were slow to hydrolyze, the acylated β‐lactamases are hydrolyzed at a much faster rate (high k 3 ).…”

“…Resistance to β‐lactams occurs through four mechanisms 140. The first two are relatively rare and only occur in Gram‐negative bacteria.…”

Enantioselective Synthesis and Profiling of Two Novel Diazabicyclooctanone β-Lactamase Inhibitors

“…However, these β-lactamase inhibitors only have activity against class A β-lactamases and weak or no activity against class C and D enzymes. 4 In addition, β-lactamases are rapidly evolving, as evident by the rising number of new β-lactamases reported each year (over 1400 to date). 7 Therefore, this urgent medical need calls for firm commitment to the discovery and development of novel and more efficient inhibitors with broader coverage of β-lactamases.…”

Phenotypic methods for screening carbapenem-resistant Enterobacteriaceae and assessment of their antimicrobial susceptibility profile

“…Sensitivity profiles of the isolates were assessed through the automated methodology Advanced Expert System (BioMérieux, France), following recommendations of the Clinical and Laboratory Standards Institute 16 . Sensitivity cards were used with the following antimicrobials: ertapenem, meropenem, imipenem, amikacin, gentamicin, norfloxacin, nitrofurantoin, sulfamethoxazole/ trimethoprim, ciprofloxacin, tigecycline, and colistin.…”