New β-lactamase inhibitors: a therapeutic renaissance in an MDR world

Abstract

As the incidence of Gram-negative bacterial infections for which few effective treatments remain increases, so does the contribution of drug-hydrolyzing β-lactamase enzymes to this serious clinical problem. This review highlights recent advances in β-lactamase inhibitors and focuses on agents with novel mechanisms of action against a wide range of enzymes. To this end, we review the β-lactamase inhibitors currently in clinical trials, select agents still in preclinical development, and older therapeutic approaches that are being revisited. Particular emphasis is placed on the activity of compounds at the forefront of the developmental pipeline, including the diazabicyclooctane inhibitors (avibactam and MK-7655) and the boronate RPX7009. With its novel reversible mechanism, avibactam stands to be the first new β-lactamase inhibitor brought into clinical use in the past 2 decades. Our discussion includes the importance of selecting the appropriate partner β-lactam and dosing regimens for these promising agents. This "renaissance" of β-lactamase inhibitors offers new hope in a world plagued by multidrug-resistant (MDR) Gram-negative bacteria.

FIG 1

(a) Chemical structures of current clinically available β-lactamase inhibitors. (b) Acylation step in general mechanism of inhibition of a class A β-lactamase by a β-lactamase inhibitor, illustrated here for clavulanic acid (4).

FIG 2

(a) Hypothesized mechanism of avibactam acylation and regeneration with a class A β-lactamase; the amine and sulfate are highlighted in yellow and blue, respectively (11). (b) Structure of MK-7655; the piperidine ring and sulfate are highlighted in yellow and blue, respectively (40). (c and d) Three-dimensional structures of avibactam (c) and MK-7655 (d), constructed using Fragment Builder tools and minimized using a Standard Dynamics Cascade protocol in Discovery Studio 3.1.

FIG 3

(a) General mechanism of reversible inhibition of a class A β-lactamase by a boronic acid compound. (b) Structure of β-lactam substrate analog boronic acid inhibitors (ampicillin, cephalothin, and cefoperazone mimics). (c) Structure of sulfonamide boronic acid (tested as described in reference 57); the sulfonamide boronic acid group is highlighted in yellow. (d) Compound 5 developed from FBLD optimization of sulfonamide boronate structure (59); the sulfonamide boronic acid group and tetrazole are highlighted in yellow and blue, respectively. (e) Structure of RPX7009 (65).

FIG 4

Structure of cyclobutanone inhibitor with high affinity for class C enzymes; the chlorine atoms are highlighted in green (68).

FIG 5

(a) Thiol compound with inhibitory activity for the three MBL classes (76). (b) Structure of thiosemicarbazide derivative and l-captopril, metallo-β-lactamase IMP-1 inhibitors (85, 87).

FIG 6

(a) Structure of EDTA. (b) Structure of LN-1-255 (108). (c) Structure of DSABA (109).

FIG 7

Structure of thiophenyl oxime-derived phosphonate compound with strong class C inhibitory activity (110).