2019 ASM Microbe Meeting,
June 20-24, 2019, San Francisco, CA
Discovery of QPX7728, an Ultra-Broad-Spectrum Inhibitor of Serine and Metallo Beta-lactamases (AAR706). Scott J. Hecker, K. Raja Reddy, Olga Lomovskaya, David C. Griffith, Debora Rubio-Aparicio, Kirk Nelson, Ruslan Tsivkovski, Dongxu Sun, Mojgan Sabet, Ziad Tarazi, Maxim Totrov, Orville Pemberton, Yu Chen, and Michael N. Dudley. The path to discovery of the ultra-broad-spectrum beta-lactamase inhibitor QPX7728, including an overview of microbiology and structural biology, will be described.
QPX7728: Spectrum of Beta-Lactamase Inhibition and Impact of Resistance Mechanisms on Activity in Gram-Negative Bacteria (AAR-707). Olga Lomovskaya, Debora Rubio-Aparicio, Kirk Nelson, Dongxu Sun and Michael Dudley. QPX7728 restores activity of multiple beta-lactam antibiotics in bacteria producing class A, C and D serine BLs, including class D carbapenemases from Acinetobacter, and major class B metallo-beta-lactamases. Excellent activity is observed in pathogens with multiple porin mutations and is not affected by efflux pumps.
QPX7728: Biochemical Characterization of Inhibitory Activity against Serine and Metallo beta-lactamases from Enterobacteriaceae and Acinetobacter (AAR-708). Ruslan Tsivkovski and Olga Lomovskaya. QPX7728 is a potent reversible inhibitor of serine and metallo-beta-lactamases. It shows slow, tight-binding inhibition of serine beta-lactamases with high enzyme inactivation efficiency and low off-rate with residence times reaching values of several hours for some enzymes.
QPX7728: In Vitro Activity in Combination with Meropenem against Carbapenem-Resistant Enterobacteriaceae (CRE) (AAR-709). Kirk Nelson, Debora Rubio-Aparicio, and Olga Lomovskaya. QPX7728 restored the potency of meropenem against CRE, with >95% of strains inhibited by QPX7728 + meropenem. Outer membrane porin mutations that restrict entry of many drugs had a lower effect on QPX7728 + meropenem compared to other recently approved beta-lactamase inhibitor combination products.
QPX7728: In Vitro Activity in Combination with Oral Beta-Lactam Antibiotics against Enterobacteriaceae (ENT) (AAR-710). Debora Rubio-Aparicio, Kirk Nelson, David C Griffith, Michael N Dudley, and Olga Lomovskaya. QPX7728 enhanced the potency of the oral beta-lactam antibiotics ceftibuten and tebipenem against Enterobacteriaceae with the ESBL phenotype as well as CRE (including KPC, OXA-48-like, and MBL producing strains).
In Vitro Activity of the β-lactamase Inhibitor QPX7728 Combined with Several β-lactams When Tested against Acinetobacter baumannii (AB) and Pseudomonas aeruginosa (PA) (AAR-711). Mariana Castanheira, Jill Lindley, Kirk Nelson, Debora Rubio-Aparicio, and Olga Lomovskaya. QPX7728 restored the potency of meropenem against carbapenem- resistant Acinetobacter baumannii, with >90% of isolates were inhibited by ≤8 µg/ml of meropenem with QPX7728 (at 4 or 8 µg/ml). In Pseudomonas, QPX7728 combinations showed high potency against a representative panel that reflects current MIC distributions for clinical isolates; in highly meropenem, ceftazidime-avibactam and ceftolozane-tazobactam resistant isolates, QPX7728 combined with meropenem or ceftolozane were the most potent combinations.
In Vivo Activity of QPX7728 in Combination with Meropenem against Carbapenem-resistant K. pneumoniae, A. baumannii, and P. aeruginosa (AAR-712). Mojgan Sabet, Ziad Tarazi, and David C. Griffith. QPX7728 plus meropenem produces dose-dependent bacterial killing of carbapenem-resistant Enterobacteriaceae (CRE), A. baumannii, and P. aeruginosa in mouse models of infection.
Pharmacokinetics of QPX7728 following IV Dosing in Non-Clinical Species (AAR-713).
Ziad Tarazi, Mojgan Sabet, Jonathan Parkinson, and David C. Griffith. The pharmacokinetics of QPX7728 following IV dosing in non-clinical species show properties consistent with co-administration with beta-lactam antibiotics.