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

> **NIH NIH R44** · VENATORX PHARMACEUTICALS, INC. · 2024 · $1,000,000

## Abstract

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.

## Key facts

- **NIH application ID:** 10773624
- **Project number:** 5R44AI170331-03
- **Recipient organization:** VENATORX PHARMACEUTICALS, INC.
- **Principal Investigator:** Bin Liu
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,000,000
- **Award type:** 5
- **Project period:** 2022-03-10 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10773624

## Citation

> US National Institutes of Health, RePORTER application 10773624, Broad spectrum β-lactamase inhibitors employing a Trojan horse mechanism to rescue β-lactams against multidrug-resistant Pseudomonas aeruginosa (5R44AI170331-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10773624. Licensed CC0.

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