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.

What Is New in the Anti–Pseudomonas aeruginosa Clinical Development Pipeline Since the 2017 WHO Alert?

“…At least four other new BLIs in association with β-lactam are on phase I stage (completed or ongoing) ( Figure 4C ): nacubactam, zidebactam, QPX7728, and XNW4107. Whereas nacubactam reported narrow in vitro activity in P. aeruginosa ( Asempa et al., 2020 ), QPX7728 is an ultra-broad-spectrum β-lactamase inhibitor with the broadest spectrum of inhibition in vitro reported to date in a single BLI molecule ( Lomovskaya et al, 2021 ). Zidebactam in association with cefepime should start a phase III in cUTI or acute pyelonephritis end of 2021 ( ).…”

Carbapenemase Inhibitors: Updates on Developments in 2021

“…When compared to the newly licensed drugs such as avibactam, vaborbactam and relebactam, QPX7728 has a wider beta-lactamase inhibitory spectrum. Drugs from this class are strong inhibitors of Enterobacteriaceae class A carbapenemases, such as KPC, class C beta-lactamases and, some class D enzymes [ 57 , 58 ]. Of note, this class was the only class among the newly licensed drugs to show significant activity against Baumannii class D carbapenems such as OXA-23, OXA 24/40 and OXA 58 as well as the B1 subclass such as NDM, VIM, and IMP [ 58 , 59 ].…”

Three-Dimensional Structure and Optimization of the Metallo-β-Lactamase Inhibitor Aspergillomarasmine A

“…1 1 Hz, 1H), 2.74 (t, J = 0.9 Hz, 3H), 2.09−2.07 (m, 1H), 1.93 (t, J = 0.9 Hz, 1H). 13 (S)-2-Amino-3-(((S)-1-carboxy-2-(((S)-1-carboxy-2hydroxyethyl)amino)ethyl)amino)propanoic Acid (19). L-Serine-substituted AMA analog 19 was synthesized according to the above general procedure using L-serine-substituted resin.…”

“…Tanirobactam has entered clinical development in combination with cefepime against carbapenem-resistant Enterobacteriaceae (CRE), carbapenem-resistant P. aeruginosa (CRPA), and NDM and VIM classes of MBL. , Additionally, QPX7728 has been shown have better activity against the IMP class of MBL . Despite this advancement, the search for broad-spectrum inhibitors of MBLs must continue since one has yet to be approved for clinical use.…”

“…17,18 Additionally, QPX7728 has been shown have better activity against the IMP class of MBL. 19 Despite this advancement, the search for broadspectrum inhibitors of MBLs must continue since one has yet to be approved for clinical use. In 2014, we identified a fungal Zn 2+ metallophore, aspergillomarasmine A 20 (AMA) (Figure 2 selective Zn 2+ binding with picomolar affinity, which sequesters the metal in complex fluids.…”