Broad spectrum β-lactamase inhibitors employing a Trojan horse mechanism to rescue β-lactams against multidrug-resistant Pseudomonas aeruginosa

Project Summary: Evolution of multiple resistance mechanisms from extensive use of antibiotics has eroded the efficacy of one of the most important classes of antibiotics, the β-lactams. The situation is particularly dire in non-fermenting gram-negative pathogens such as Pseudomonas aeruginosa, where not only β-lactamase enzymes (i.e., PDC, PER, and VIM) drive resistance but the outer membrane in concert with efflux serves as a formidable barrier to antibiotic entry. This 3-year SBIR Direct-to-Phase II Application centers on completing the lead optimization of a unique catechol-conjugated β-lactamase inhibitor (CC-BLI) series able to take advantage of facilitated entry and offering an unprecedented level of activity against Multidrug-Resistant (MDR) Pseudomonas when combined with ceftolozane (currently marketed as Zerbaxa®). The commercial presentation of Zerbaxa® is intravenous ceftolozane combined with the legacy β-lactamase inhibitor tazobactam; however, tazobactam fails to protect ceftolozane from Ambler class C Pseudomonas-derived cephalosporinases (PDC), as well as class A (KPC), B (VIM and NDM), and D (OXA) carbapenemase. In addition to enhanced entry the CC-BLI series has activity against serine and metallo-β-lactamase enzymes including those that hydrolyze carbapenems. At the completion of lead optimization, the resulting Preclinical Development Candidate will be paired with ceftolozane (TOL), which best supports the potent activity in P. aeruginosa. This candidate TOL/CC-BLI combination will be advanced through Non-GLP toxicology activities and eventually to IND filing and approval. Ultimately, it is envisioned that this new combination product will provide a unique clinical option for empiric therapy of MDR non-fermenter infections in the hospital general ward and ICU and as a second-line therapy for susceptible organisms.