Phase I Amount
$1,000,000
Evolution of multiple resistance mechanisms from extensive use of antibiotics has eroded the efficacy of one of the most important classes of antibiotics, the ß-lactams. The situation is particularly dire in non-fermenting gram-negative pathogens such as Pseudomonas aeruginosa, where not only ß-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 ß-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 ß-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-ß-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.
Public Health Relevance Statement: Project narrative: We are optimizing to 1st Preclinical Candidate a class of catechol conjugated ß -lactamase inhibitors (CC-BLI) that protect and potentiate ß-lactams against Multidrug-Resistant (MDR) Pseudomonas aeruginosa. The compounds will be paired ultimately with ceftolozane, which best supports the potent antibacterial activity, and advanced through Non-GLP toxicology and eventually through IND-enabling activities. The intravenously administered combination would represent a powerful new treatment option against the most problematic, MDR pathogens in the hospital setting.
Project Terms: inhibitor; Antibiotics; Antibiotic Agents; Antibiotic Drugs; Miscellaneous Antibiotic; Bacteria; Carbapenems; Catechols; 1,2-benzenediol; 1,2-dihydroxybenzene; 2-hydroxyphenol; Pyrocatechols; o-Dihydroxybenzenes; ortho-Dihydroxybenzenes; Ceftazidime; Cells; Cell Body; Chemistry; Pharmaceutical Chemistry; Medicinal Chemistry; Pharmaceutic Chemistry; Down-Regulation; Downregulation; Enzymes; Enzyme Gene; Epidemiology; epidemiologic; epidemiological; Evolution; Family; Grant; Equus caballus; Domestic Horse; Equine; Equine Species; Equus przewalskii; Horses; Hospitals; General Hospitals; Hydrolysis; In Vitro; Infection; Lead; Pb element; heavy metal Pb; heavy metal lead; Microbiology; Mus; Mice; Mice Mammals; Murine; living system; Organism; Plasma Proteins; Production; Chrysemonas; Flavimonas; Pseudomonas; P aeruginosa; P. aeruginosa; Pseudomonas pyocyanea; Pseudomonas aeruginosa; Research; Rodentia; Rodents Mammals; Rodent; L-Serine; Serine; Solubility; Thigh; Thigh structure; Toxicology; General Ward; Tazobactam; Generations; base; Clinical; Phase; Medical; Series; pediatric; Childhood; Ligand Binding Protein; Ligand Binding Protein Gene; Protein Binding; bound protein; Binding Proteins; Multidrug Resistance; Multiple Drug Resistance; Multiple Drug Resistant; Resistance to Multi-drug; Resistance to Multidrug; Resistance to Multiple Drug; Resistant to Multiple Drug; Resistant to multi-drug; Resistant to multidrug; multi-drug resistant; multidrug resistant; Multi-Drug Resistance; Beta-Lactam resistant; b lactam resistance; b-lactam resistant; resistance to b lactam; resistance to beta-lactam; resistance to ß-Lactam; resistant to b lactam; resistant to beta-lactam; resistant to ß-Lactam; ß-Lactam Resistance; ß-Lactam resistant; beta-Lactam Resistance; Funding; uptake; Ccra beta-lactamase; carbapenemase; Chemosensitization/Potentiation; Potentiation; Chemosensitization; Antibacterial Agents; anti-bacterial; antibacterial; Anti-Bacterial Agents; ß-Lactams; beta-Lactams; Fe element; Iron; Intravenous; System; Periplasmic Space; periplasmic; periplasm; Lytotoxicity; cytotoxicity; membrane structure; Membrane; success; G24 protein; beta lactam hydrolase; beta-Lactamhydrolase; ß-Lactamase; beta-Lactamase; novel; Cephalosporin Amido-beta-Lactam Hydrolase; Cephalosporin beta-Lactamase; beta-Lactamase II; Cephalosporinase; Property; VDAC1; pore forming protein; porin; VDAC1 gene; Dose; Absorption, Distribution, Metabolism, and Excretion Study; ADME Study; Grant Proposals; Applications Grants; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; resistance mechanism; resistant mechanism; Development; developmental; pre-clinical; preclinical; scale up; pathogen; Population; Resistance; resistant; FDA approved; resistant strain; resistance strain; lead series; multi-drug resistant pathogen; MDR organism; MDR pathogen; multi-drug resistant organism; multidrug resistant organism; multidrug resistant pathogen; multiple drug resistant organism; multiple drug resistant pathogen; multidrug-resistant Pseudomonas aeruginosa; MDR P aeruginosa; MDR P. aeruginosa; MDR Pseudomonas aeruginosa; multi-drug resistant P. aeruginosa; multi-drug resistant Pseudomonas aeruginosa; multidrug resistant P. aeruginosa; multidrug-resistant P. aeruginosa; Formulation; clinical candidate; preclinical development; pre-clinical development; lead optimization; pneumonia model; pneumonia models; pharmacokinetics and pharmacodynamics; PK/PD
