The Ultrabroad-Spectrum Beta-Lactamase Inhibitor QPX7728 Restores the Potency of Multiple Oral Beta-Lactam Antibiotics against Beta-Lactamase-Producing Strains of Resistant Enterobacterales

Abstract

QPX7728 is a cyclic boronate ultrabroad-spectrum beta-lactamase inhibitor, with potent activity against both serine beta-lactamases and metallo-beta-lactamases. QPX7728 can be delivered systemically by the intravenous (i.v.) or oral route of administration. Oral beta-lactam antibiotics alone or in combination with QPX7728 were evaluated for (i) sensitivity to hydrolysis by various common beta-lactamases and inhibition of hydrolysis by QPX7728, (ii) the impact of non-beta-lactamase-mediated resistance mechanisms on potency of beta-lactams, and (iii) in vitro activity against a panel of clinical strains producing diverse beta-lactamases. The carbapenem tebipenem had stability for many serine beta-lactamases from all molecular classes, followed by the cephalosporin ceftibuten. Addition of QPX7728 to tebipenem, ceftibuten, and amdinocillin completely reversed beta-lactamase-mediated resistance in cloned betalactamases from serine enzyme and metalloenzyme classes; the degree of potentiation of other beta-lactams varied according to the beta-lactamase produced. Tebipenem, ceftibuten, and cefixime had the lowest MICs against laboratory strains with various combinations of beta-lactamases and the intrinsic drug resistance mechanisms of porin and efflux mutations. There was a high degree of correlation between potency of various combinations against cloned beta-lactamases and efflux/porin mutants and the activity against clinical isolates, showing the importance of inhibition of beta-lactamase along with minimal impact of general intrinsic resistance mechanisms affecting the beta-lactam. Tebipenem and ceftibuten appeared to be the best beta-lactam antibiotics when combined with QPX7728 for activity against Enterobacterales that produce serine beta-lactamases or metallo-beta-lactamases.