Design, Synthesis, and Evaluation of 2β-Alkenyl Penam Sulfone Acids as Inhibitors of β-Lactamases

Abstract

A general method for synthesis of 2 beta-alkenyl penam sulfones has been developed. The new compounds inhibited most of the common types of beta-lactamase. The level of activity depended very strongly on the nature of the substituent in the 2 beta-alkenyl group. The inhibited species formed with the beta-lactamase from Citrobacter freundii 1205 was sufficiently stable for X-ray crystallographic studies. These, together with UV absorption spectroscopy and studies of chemical degradation, suggested a novel reaction mechanism for the new inhibitors that might account for their broad spectrum of action. The (Z)-2 beta-acrylonitrile penam sulfone Ro 48-1220 was the most active inhibitor from this class of compound. The inhibitor enhanced the action of, for example, ceftriaxone against a broad selection of organisms producing beta-lactamases. The organisms included strains of Enterobacteriaceae that produce cephalosporinases, which is an exceptional activity for penam sulfones.

Three Decades of β-Lactamase Inhibitors

“…Inhibition with Ro 48-1220 was as effective as tazobactam for TEM-1 and SHV-1, with IC 50 s within 0.03 M for both enzymes. Most class C enzymes tested were inhibited at lower concentrations of Ro 48-1220 than of tazobactam (IC 50 range approximately 2-to 30-fold lower) (367,422). The IC 50 s for X. maltophilia and Bacteroides fragilis class B enzymes were 24 and 200 M, in comparison to 4 and Ͼ10 mM for tazobactam (367).…”

“…C-2/C-3-substituted penicillin and cephalosporin sulfones. ␤-Lactamase inhibitors with C-2 substitutions have shown efficacy against TEM-and SHV-type enzymes, including ESBLs (367,422). The acrylonitrile derivative Ro 48-1220 (Fig.…”

New Treatment Options against Gram-negative Organisms

“…Richter et al demonstrated that Ro 48-1220, the most active inhibitor from this class of compounds, enhanced the action of ceftriaxone against a broad selection of organism producing β-lactamases, including strains of cephalosporinase-producing Enterobacteriaceae [25]. In a diff erent study, Ro 48-1220 was at least 15 times more eff ective than tazobactam against the class C enzymes and reduced the MIC values of ceftriaxone and ceftazidime against the class A plasmid-mediated β-lactamases; less potency was exerted towards SHV-type β-lactamases [26].…”

Evaluation of β-Lactamase Inhibitors in Disk Tests for Detection of Plasmid-Mediated AmpC β-Lactamases in Well-Characterized Clinical Strains of Klebsiella spp

“…Using 20 well-characterized positive and negative control strains, the inhibitor-based test showed the potential for the detection of organisms producing plasmid-mediated AmpC ␤-lactamases of cefotetan in combination with LN-2-128 and 48-1220. LN-2-128 and 48-1220 are inhibitors of class A ␤-lactamases in addition to AmpC ␤-lactamases (4,22). A novel AmpC ␤-lactamase inhibitor, Syn 2190 (Naeja Pharmaceutical Inc., Edmonton, Alberta, Canada), does not inhibit class A ␤-lactamases (18).…”