# Innovative technologies to transform antibiotic discovery. Project 4 Infection site-specific amplification of antimicrobial conjugates

> **NIH NIH U19** · BROAD INSTITUTE, INC. · 2020 · $1,378,141

## Abstract

ABSTRACT
 Drugging Gram-negative bacteria in the clinic is an urgent unmet need due to rapidly-evolving resistant
strains, the inability of conventional antibiotics to penetrate the outer cell wall, and off-target in vivo drug toxicities.
Antimicrobial peptides (AMPs) and other small molecule antibacterial leads have shown promise in preclinical
testing for killing multi-drug resistant Gram-negative pathogens, but have faced significant challenges in clinical
translation as a result of inferior therapeutic outcomes in vivo. This proposal addresses the shortage of novel
treatment strategies for multi-drug resistant Gram-negative pathogens by exploiting the pathogen's cell surface
glycans and local environment to deliver antimicrobial payloads. Long-circulating, pro-drug constructs will be
engineered that selectively target the site of infection after systemic administration and activate in response to
proteolytic activity specific to the infected tissue microenvironment. The proposed antimicrobial agents, termed
antimicrobial conjugates (AMCs) consist of a pathogen-specific targeting agent, a microenvironment-specific
cleavable linker, and a bactericidal payload. This modular design allows the exploration of different components
to optimize the conjugate's activity. The proposed AMCs will be designed and extensively evaluated in vitro and
in animal models for toxicity and antimicrobial activity by a joint team at MIT composed of Drs. Sangeeta Bhatia,
Timothy Lu, Laura Kiessling, and Bradley Pentelute. Their labs will leverage expertise with protease-responsive
nanomaterials, synthetic biology and computational design, protein-glycan recognition processes, and
bioconjugation and rapid peptide synthesis technologies, respectively, to advance the development of AMCs.
 This new therapeutic modality has several advantages: the high level of specificity for pathogen targets will
limit toxicity to host, enabling the use of less selective antimicrobial agents, the conjugates will have increased
pharmacokinetics, and the narrow spectrum activity will avoid the spread of general resistance mechanisms
between species and limit damage to the host microbiota. Completion of the project will generate lead
antimicrobial conjugates for the treatment of resistant Gram-negative infections. Collectively optimizing the
therapeutic profiles of lead compounds will identify top candidates that can be advanced for pre-clinical trials,
with the potential to deliver a therapeutic strategy that effectively bypasses acquired Gram-negative antibiotic
resistance.

## Key facts

- **NIH application ID:** 9990695
- **Project number:** 5U19AI142780-02
- **Recipient organization:** BROAD INSTITUTE, INC.
- **Principal Investigator:** DEBORAH T HUNG
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,378,141
- **Award type:** 5
- **Project period:** 2019-08-07 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990695

## Citation

> US National Institutes of Health, RePORTER application 9990695, Innovative technologies to transform antibiotic discovery. Project 4 Infection site-specific amplification of antimicrobial conjugates (5U19AI142780-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9990695. Licensed CC0.

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