Summary: Since 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 serious Enterobacteriaceae and 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.

Three Decades of β-Lactamase Inhibitors

Chiral thiourea 1b catalyzes the highly enantioselective hydrophosphonylation of a wide range of N-benzyl imines. The hydrophosphonylation products are readily deprotected by hydrogenolysis, providing access to free alpha-amino phosphonic acids in highly enantioenriched form.

Thiourea-catalyzed enantioselective hydrophosphonylation of imines: practical access to enantiomerically enriched alpha-amino phosphonic acids.

An Overview of Stereoselective Synthesis of α-Aminophosphonic Acids and Derivatives

Copper-catalyzed aerobic phosphonation of sp3 C–H bonds

The beta-lactamase cycle: a tale of selective pressure and bacterial ingenuity.

A phosphonate monoester, m-carboxyphenyl phenylacetamidomethylphosphonate, has been found to be a specific inhibitor of the class C beta-lactamase of Enterobacter cloacae P99. Inactivation is rapid (10(3) per second per molar concentration) and reactivation very slow (2.2 X 10(-6) per second). Apparently concerted with the inactivation, one equivalent (with respect to the enzyme) of m-hydroxybenzoate is released. Reactivation is accelerated by hydroxylamine and benzohydroxamate. This suggests that the loss of enzyme activity is due to phosphonylation of an active site functional group. This discovery holds the promise of a new general class of beta-lactamase inhibitors and, perhaps, antibiotics.

https://science.sciencemag.org/content/sci/246/4932/917.full.pdf

R F Pratt

Papers

Inhibition of a class C beta-lactamase by a specific phosphonate monoester