New β-Lactamase Inhibitors in the Clinic

Abstract

Given the serious medical burden of β-lactamases, many approaches are being used identify candidate agents for β-lactamase inhibition. Here, we review two β-lactam-β-lactamase inhibitor (BL-BLI) combinations, ceftolozane-tazobactam and ceftazidime-avibactam that recently entered the clinic. In addition, we focus on BL-BLI combinations in preclinical development that have demonstrated activity in clinical isolates via susceptibility testing and/or in in vivo models of infection. We highlight only the BLIs that are able to reduce the Clinical Laboratory Standards Institute (CLSI) breakpoints for the BL partner into the susceptible range. Our analysis includes the primary literature, meeting abstracts, as well as the patent literature.

Keywords: Boronic acids; Carbapenems; Diazabicyclooctanones; Inhibitor; Metallo-beta-lactamases; Monobactams; Sulfones; β-Lactamases.

Fig. 1

β-Lactamase inhibitors of the past and their β-lactam partners.

Fig. 2

Chemical structure of ceftolozane.

Fig. 3

DBOs and DBO β-lactam partners.

Fig. 4

Chemical structures of the carbavance (meropenem-RPX7009) combination, biapenem, and other boronates.

Fig. 5

Chemical structures of AAI101 and cefepime.

Fig. 6

Phosphonate, MG96077.

Fig. 7

Chemical structures of monobactams and bridged monobactams.

Fig. 8

Chemical structure of 3′-thiobenzoyl cephalosporins.

Fig. 9

Chemical structures of FSI-1671 and FSI-1686.

Fig. 10

Chemical structure of MBL-specific inhibitors the BTZ, (3R,5R,7aS)-5-(sulfanylmethyl) tetrahydro[1,3] thiazol[4,3-b][1,3]thiazole-3-carboxylic acid and ME1071.