β-lactam/β-lactamase inhibitor combinations: an update

Abstract

Antibiotic resistance caused by β-lactamase production continues to present a growing challenge to the efficacy of β-lactams and their role as the most important class of clinically used antibiotics. In response to this threat however, only a handful of β-lactamase inhibitors have been introduced to the market over the past thirty years. The first-generation β-lactamase inhibitors (clavulanic acid, sulbactam and tazobactam) are all β-lactam derivatives and work primarily by inactivating class A and some class C serine β-lactamases. The newer generations of β-lactamase inhibitors including avibactam and vaborbactam are based on non-β-lactam structures and their spectrum of inhibition is extended to KPC as an important class A carbapenemase. Despite these advances several class D and virtually all important class B β-lactamases are resistant to existing inhibitors. The present review provides an overview of recent FDA-approved β-lactam/β-lactamase inhibitor combinations as well as an update on research efforts aimed at the discovery and development of novel β-lactamase inhibitors.

Fig. 1. A. β-lactam inactivation mediated by serine β-lactamases (ambler class A, C and D) is facilitated by the attack of a nucleophilic serine. B. MBL (class B)-mediated inactivation of β-lactams involves a nucleophilic attack by an activated water molecule coordinated to zinc ions.

Fig. 2. β-lactam antibiotics evaluated in combination with β-lactamase inhibitors.

Fig. 3. First generation of β-lactamase inhibitors; clavulanic acid 14, sulbactam 15 and tazobactam 16.

Fig. 4. Vaborbactam 17.

Fig. 5. Avibactam 18.

Fig. 6. SBL inhibitor penam sulfones AAI101 (19) and LN-1-255 (20).

Fig. 7. Diazabicyclooctanes in clinical development: relebactam 21, zidebactam 22, nacubactam 23, ETX2514 24.

Fig. 8. DBO analogs as β-lactamase inhibitors reported in the recent patents.

Fig. 9. Representative boronic acids as β-lactamase inhibitors.

Fig. 10. A. Tetrahedral intermediate formed by nucleophilic attack of SBLs (Nu: = serine-OH) and MBLs (Nu: is zinc-coordinated OH^–) on β-lactam ring. B. Cyclic boronates mimicking the tetrahedral transition state of β-lactam hydrolysis.,

Fig. 11. Thiol-containing MBL inhibitors, thiorphan 39, captopril 40 and substituted mercaptoacetamides 41.

Fig. 12. Pyridine derivatives as MBL-inhibitors.

Fig. 13. Dicarboxylic acid analogs as MBL-inhibitors.

Fig. 14. Zinc chelators 52–57 and other unique compounds with MBL inhibitory activity.