# Exploiting membrane targets to overcome antibiotic resistance

> **NIH NIH U19** · HARVARD MEDICAL SCHOOL · 2022 · $2,410,919

## Abstract

PROJECT SUMMARY – Overall
Antibiotic resistance is a major public health concern worldwide. This CARB (Combating Antibiotic Resistant
Bacteria) proposal was conceived in response to this urgent global threat. The theme of our program, “Exploiting
Membrane Targets to Overcome Antibiotic Resistance,” addresses important gaps in current knowledge to
facilitate translation of discoveries into strategies to combat antibiotic-resistant infections. A team of highly
collaborative and productive scientists from diverse fields – chemistry, biochemistry, structural biology, and
molecular genetics – has joined forces in this effort. The cell envelope, the interface between host and pathogen,
is a major point of vulnerability for bacteria. Interfering with cell envelope assembly or function can inhibit bacterial
growth, promote lysis, decrease resistance to host immune defenses, and increase susceptibility to other
antibiotics to overcome resistance. Identifying and exploiting new ways of disrupting envelope assembly
pathways to enable therapeutic discovery has been an important goal in the field. However, progress in this area
has been hampered by the many challenges posed by envelope targets. Biosynthetic and regulatory processes
that govern cell envelope biogenesis take place at a membrane interface and often involve proteins that contain
multiple membrane-spanning segments, function in multi-protein complexes, and use complicated substrates
that are not commercially available. Advancing our understanding of these cell envelope targets requires the
concerted efforts of an interdisciplinary team with expertise that spans broad areas of chemistry and biology.
Recent technological advances and biological discoveries, many made by the CARB project team, have
transformed our understanding of cell envelope biology and opened the door to fundamentally new approaches
to therapeutic targeting of this essential structure. To build on these successes, we have created a collaborative,
interdisciplinary project to identify, characterize, and validate novel vulnerabilities in envelope biogenesis and
maintenance pathways. The three proposed projects are not only connected by the shared focus of the
investigators on cell envelope biology, their commitment to molecular mechanism as the foundation of
translational research, and overlapping themes and goals, but also by synergistic collaboration among multiple
investigators within as well as between each proposal. Project 1 will define the structural basis for enzymatic
activity of the broadly conserved SEDS family cell wall polymerases and determine how SEDS proteins function
within large macromolecular complexes during growth and division. Project 2 will focus on identifying and
exploiting vulnerabilities in the Gram-positive cell envelope. Project 3 will focus on characterizing and exploiting
vulnerabilities in the Gram-negative cell envelope. A streamlined administrative core will coordinate activities to
maximize synerg...

## Key facts

- **NIH application ID:** 10169871
- **Project number:** 1U19AI158028-01
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Suzanne Walker
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,410,919
- **Award type:** 1
- **Project period:** 2022-09-07 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10169871

## Citation

> US National Institutes of Health, RePORTER application 10169871, Exploiting membrane targets to overcome antibiotic resistance (1U19AI158028-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10169871. Licensed CC0.

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