Impact of Intrinsic Resistance Mechanisms on Potency of QPX7728, a New Ultrabroad-Spectrum Beta-Lactamase Inhibitor of Serine and Metallo-Beta-Lactamases in Enterobacteriaceae , Pseudomonas aeruginosa, and Acinetobacter baumannii

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.

In Vitro Activity of the Ultrabroad-Spectrum-Beta-Lactamase Inhibitor QPX7728 against Carbapenem-Resistant Enterobacterales with Varying Intrinsic and Acquired Resistance Mechanisms

“…In agreement with our data from laboratory-derived strains (12), the inactivation of OmpK35 did not affect the potency of QPX7728; the meropenem MIC distributions in the presence of QPX7728 at 4 g/ml or 8 g/ml remained very similar for isolates with either functional or nonfunctional OmpK35/OmpF (the meropenem MIC 90 with 4 or 8 g/ml of QPX7728 was 4 g/ml or 0.5 g/ml, respectively, compared to Ͼ64 g/ml for meropenem alone) (Table S4a). Defects in OmpK36/OmpC were associated with changes in meropenem-QPX7728 MIC distributions; the MIC 90 of meropenem in the presence of QPX7728 was increased 16-to 32-fold (Table 4 and Table S4b) from 0.25 g/ml to 8 g/ml and from Յ0.06 g/ml to 1 g/ml for QPX7728 at 4 g/ml and 8 g/ml, respectively.…”

“…The higher proportion of MBL-positive strains inhibited by QPX7728 alone might be due to the lower proportion of strains that carry nonfunctional OmpK36/OmpC (Fig. S2), as QPX7728 apparently uses this porin to cross the outer membrane (as inferred from the experiments with K. pneumoniae) (12).…”

“…QPX7728 in combination with meropenem has excellent potency against CRE with permeability defects due to porin mutations. We have recently shown that the potency of QPX7728 was reduced (albeit to a much lesser degree than vaborbactam) in strains that carried nonfunctional or partially functional porin OmpK36 (12). To extend this work, we assessed the reduction in meropenem MICs with various concentrations of QPX7728 in a subset of isolates that carried various defects in OmpK36/ OmpC and OmpK35/OmpF to determine the QPX7728 TPC 90 against this panel of strains.…”

“…Class B subclass B1 metallo-enzymes, NDM, VIM, some IMPs, GIM-1, and CcrA, are inhibited by QPX7728 (11). Using a panel of isogenic strains of Klebsiella pneumoniae with or without inactivation of the major general porins OmpK35/OmpF and OmpK36/OmpC, the potency of QPX7728 in Enterobacterales was affected much less than the potency of vaborbactam (12).…”

<p>A Clinical Review and Critical Evaluation of Imipenem-Relebactam: Evidence to Date</p>

“…These include nacubactam (formerly RG6080 and OP05095), zidebactam (formerly WXK 5107) taniborbactam (formerly VNRX-5133), enmetazobactam (formerly AAI-101), durlobactam (formerly ETX-2514), and QPX-7728. [59][60][61][62][63][64] These may represent future alternative treatment options given the increase in resistant gram-negative infections.…”