QPX7728, An Ultra-Broad-Spectrum B-Lactamase Inhibitor for Intravenous and Oral Therapy: Overview of Biochemical and Microbiological Characteristics

Abstract

QPX7728 is a novel β-lactamase inhibitor (BLI) that belongs to a class of cyclic boronates. The first member of this class, vaborbactam, is a BLI in the recently approved Vabomere (meropenem-vaborbactam). In this paper we provide the overview of the biochemical, structural and microbiological studies that were recently conducted with QPX7728. We show that QPX7728 is an ultra-broad-spectrum β-lactamase inhibitor with the broadest spectrum of inhibition reported to date in a single BLI molecule; in addition to potent inhibition of clinically important serine β-lactamases, including Class A and D carbapenemases from Enterobacterales and notably, diverse Class D carbapenemases from Acinetobacter, it also inhibits many metallo β-lactamases. Importantly, it is minimally affected by general intrinsic resistance mechanisms such as efflux and porin mutations that impede entry of drugs into gram-negative bacteria. QPX7728 combinations with several intravenous (IV) β-lactam antibiotics shows broad coverage of Enterobacterales, Acinetobacter baumannii and Pseudomonas aeruginosa, including strains that are resistant to other IV β-lactam-BLI combinations, e.g., ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam and imipenem-relebactam that were recently approved for clinical use. Based on studies with P. aeruginosa, different partner β-lactams in combination with QPX7728 may be optimal for the coverage of susceptible organisms. This provides microbiological justification for a stand-alone BLI product for co-administration with different β-lactams. QPX7728 can also be delivered orally; thus, its ultra-broad β-lactamase inhibition spectrum and other features could be also applied to oral QPX7728-based combination products. Clinical development of QPX7728 has been initiated.

Keywords: Acinetobacter; CRE; Pseudomonas; QPX7728; beta-lactamase inhibitor; carbapenemase; metallo β-lactamase.

FIGURE 1

Evolution of boronic β-lactamase inhibitors.

FIGURE 2

High resolution structures of QPX7728 with KPC-2, OXA-48, NDM-1, and VIM-2. Accession codes are the following: 6V1J (KPC-2: QPX7728), 6V1M (NDM-1: QPX7728), 6V1O (OXA-48: QPX7728), and 6V1P (VIM-2: QPX7728). Modified from Hecker et al. (2020).

FIGURE 3

High resolution structures of RPX7728 with multiple enzymes: superimposition of β-lactamases using the ligand. (A) The aromatic/lipophilic interactions are shown. (B) Close-up of carboxylate interactions and orientation.

FIGURE 4

(A) Comparison of QPX7728 and vaborbactam in complex with KPC-2 with carbon atoms of QPX7728 and vaborbactam in light brown and in yellow carbon atoms, respectively [accession codes are the following: 6V1J (KPC-2:QPX7728); 6TD0 (KPC-2:vaborbactam)]. (B) Superposition of QPX7728 (crème carbon atoms) and the core ring system of penem antibiotics (magenta carbon atoms).

FIGURE 5

Analysis of interactions of QPX7728 with NDM-1 and L1 B-Lactamases. (A) The crystal structure of QPX7728/NDM-1 complex. (B) Model of the putative QPX7728/L1 complex. Modified from Lomovskaya et al. (2020b).

FIGURE 6

MIC distributions of various antibiotics with increasing concentrations of QPX7728 against ESBL and carbapenemase-producing Enterobacterales (A–C) and carbapenem-resistant Acinetobacter baumannii (D). (A) Meropenem alone and with QPX7728 tested against the panel of 598 CRE isolates that contained 285 KPC, 39 OXA-48, 50 non-carbapenemase-producing CRE and 224 MBL-producing strains (149 NDM, 51 VIM, 19 IMP). (B) Cefepime or aztreonam (C) alone and in combination with QPX7728 tested against the panel of 756 strains of Enterobacterales with characterized β-lactamases; in addition to class A ESBLs and various class C enzymes it contained 302 KPC (9 in combination with MBLs), 70 OXA-48-like and 224 MBLs. (D) Meropenem alone and with QPX7728 tested against the panel of 275 carbapenem-resistant strains of A. baumannii. Figures are constructed based on data in Nelson et al. (2020a; 2020b).

FIGURE 7

MIC distributions of various β-lactam/BLI combinations against carbapenem-resistant Enterobacterales according to the type of CRE. MEM, meropenem; CAZ, ceftazidime; IMI, imipenem; AVI, avibactam; QPX, QPX7728; REL, relebactam; Non-CP CRE, non-carbapenemase producing CRE. Adapted with modifications from Nelson et al. (2020a).