# Mechanism of membrane fusion involving the Gram-negative bacteria outer membrane

> **NIH NIH SC1** · CITY COLLEGE OF NEW YORK · 2024 · $378,250

## Abstract

PROJECT SUMMARY/ABSTRACT
Gram-negative bacteria constitute the majority of antibiotic resistant organisms identified as urgent threats to
human health by the Center for Disease Control and Prevention. A major reason why Gram-negative bacteria
are resistant to modern antibiotics is the impermeable nature of their outer membrane lipopolysaccharide (LPS)
layer. This impermeable nature is due to the strong lateral interaction between neighboring LPS molecules that
includes lipid A, the core saccharide, and the O-antigen. Nanotherapeutics capable of overcoming this barrier to
successfully deliver antibiotics to Gram-negative bacteria will be of immense importance for human health. It is
our intent to develop such nanotherapeutics by using the knowledge attained from delineating the mechanism
by which a Gram-negative bacteriophage fuses its external bacterial phospholipid (BPL) membrane with the
LPS of its host for initiating infection. Embedded into the Cystovirus BPL are multimeric protein complexes,
referred to as spikes, that recognize the Gram-negative host and perform fusion. These proteins are analogous
to, but different from, the better studied eukaryotic proteins responsible for membrane fusion (e.g. HIV env, West
Nile Virus glycoprotein E, and Herpesviridae gB protein). The intent of this proposal is to investigate the
mechanism by which spikes from three different members of the Cystovirus family recognize their hosts and
drive membrane fusion. The goals of this proposal are to determine the structure of the spikes for establishing a
structural scaffold for biochemical and biophysical studies (Aim 1), determine the mechanism of cellular
recognition (Aim 2), and determine the biochemical determinants responsible for LPS- BPL fusion (Aim 3). The
long-term goal of this project is to use the spikes for delivery of antibiotics to specific strains of pathogenic Gram-
negative bacteria.

## Key facts

- **NIH application ID:** 10824419
- **Project number:** 5SC1GM139701-04
- **Recipient organization:** CITY COLLEGE OF NEW YORK
- **Principal Investigator:** Reza Khayat
- **Activity code:** SC1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $378,250
- **Award type:** 5
- **Project period:** 2021-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10824419

## Citation

> US National Institutes of Health, RePORTER application 10824419, Mechanism of membrane fusion involving the Gram-negative bacteria outer membrane (5SC1GM139701-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10824419. Licensed CC0.

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