Abstract
QPX7728 is an ultrabroad-spectrum boronic acid beta-lactamase inhibitor that demonstrates inhibition of key serine and metallo-beta-lactamases at a nanomolar concentration range in biochemical assays with purified enzymes. The broad-spectrum inhibitory activity of QPX7728 observed in biochemical experiments translates into enhancement of the potency of many beta-lactams against strains of target pathogens producing beta-lactamases. The impacts of bacterial efflux and permeability on inhibitory potency were determined using isogenic panels of KPC-3-producing isogenic strains of Klebsiella pneumoniae and Pseudomonas aeruginosa and OXA-23-producing strains of Acinetobacter baumannii with various combinations of efflux and porin mutations. QPX7728 was minimally affected by multidrug resistance efflux pumps either in Enterobacteriaceae or in nonfermenters, such as P. aeruginosa or A. baumannii Against P. aeruginosa, the potency of QPX7728 was further enhanced when the outer membrane was permeabilized. The potency of QPX7728 against P. aeruginosa was not affected by inactivation of the carbapenem porin OprD. While changes in OmpK36 (but not OmpK35) reduced the potency of QPX7728 (8- to 16-fold), QPX7728 (4 μg/ml) nevertheless completely reversed the KPC-mediated meropenem resistance in strains with porin mutations, consistent with the lesser effect of these mutations on the potency of QPX7728 compared to that of other agents. The ultrabroad-spectrum beta-lactamase inhibition profile, combined with enhancement of the activity of multiple beta-lactam antibiotics with various sensitivities to the intrinsic resistance mechanisms of efflux and permeability, indicates that QPX7728 is a useful inhibitor for use with multiple beta-lactam antibiotics.
Highlights
QPX7728 is an ultrabroad-spectrum boronic acid beta-lactamase inhibitor that demonstrates inhibition of key serine and metallo-beta-lactamases at a nanomolar concentration range in biochemical assays with purified enzymes
A set of isogenic KPC-producing strains of K. pneumoniae with various combinations of efflux and porin mutations was used to investigate the contribution of porins and efflux to the broad-spectrum inhibitory activity of QPX7728 in K. pneumoniae [22]
The potent inhibitory activity of QPX7728 in whole cells is driven in part by a lack of efflux by major transporters from Gram-negative bacteria at concentrations that are relevant for beta-lactamase inhibition
Summary
QPX7728 is an ultrabroad-spectrum boronic acid beta-lactamase inhibitor that demonstrates inhibition of key serine and metallo-beta-lactamases at a nanomolar concentration range in biochemical assays with purified enzymes. QPX7728 inhibits class A extended-spectrum beta-lactamases and carbapenemases, such as KPC, as well as the class C beta-lactamase P99 with a potency that is comparable to or higher than that of the recently FDA-approved BLIs avibactam, relebactam, and vaborbactam Unlike those other BLIs, QPX7728 is a potent inhibitor of class D carbapenemases, such as OXA-48 from Enterobacteriaceae and OXA enzymes from Acinetobacter baumannii, as well as MBLs, such as NDM-1, VIM-1, and IMP-1. The broad-spectrum inhibitory activity of QPX7728 observed in biochemical experiments translates into enhancement of the activity of many beta-lactams against extended-spectrum-beta-lactamase- and carbapenemase (serine betalactamase and metallo-beta-lactamase)-producing strains of Enterobacteriaceae, carbapenemase (OXA)-producing strains of Acinetobacter baumannii, and multidrug-resistant (MDR) strains of Pseudomonas aeruginosa [1]. This inhibitory activity of QPX7728 can be demonstrated in mouse thigh and lung infection models of infections, where meropenem showed efficacy against KPC-producing strains of Enterobacteriaceae (Klebsiella pneumoniae and Enterobacter cloacae), OXA23-producing strains of A. baumannii, and multidrug-resistant strains of P. aeruginosa that did not respond to meropenem alone [8]
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