# Biophysical understanding of pathogen-host membrane protein interactions for drug discovery and delivery

> **NIH NIH R35** · UNIVERSITY OF VIRGINIA · 2020 · $381,538

## Abstract

Many membrane proteins mediate bacterial pathogenesis and host interactions. These proteins are not the
more commonly investigated channels, transporters, and GPCRs and, therefore, provide new knowledge about
membrane protein structure, function, and dynamics. Bacterial membrane proteins are targets of antibiotics for
which resistance is a great threat. In addition, bacterial membrane proteins that interact with hosts have
evolved functions that are attractive to therapeutic delivery technologies (e.g. receptor-mediated uptake). This
MIRA application outlines our recent endeavors in understanding several different bacterial membrane
proteins, as well as, fruitful collaborations bridging biophysics to different biomedical fields. Opa proteins from
Neisseria gonorrhoeae and N. meningitidis are outer membrane proteins that bind to various host receptors
that induce engulfment of the bacterium. Several of these receptors are overexpressed in cancers and may
provide a target for therapeutic delivery. Knowledge of the structure, dynamics, and specific interactions of Opa
proteins and receptors will be used to design targeted liposome delivery to human cells. We have begun to
understand the Opa structure and have preliminary data on the interactions between Opa and the receptor
CEACAM1. In addition, we have successfully created Opa-liposomes that induce receptor-mediated
phagocytosis. Future directions focus on a multidisciplinary approach to understanding the determinants of
Opa-receptor selectivity and engineer therapeutic delivery liposomes based on the interaction. Another
function of interest to therapeutic delivery, is cellular tracking and controlling cellular fate. IncA, from
Chlamydiae, hijacks host trafficking by interacting with host SNAREs allowing the bacterium to avoid lysosomal
degradation. We propose a variety of biophysical and structural approaches to understanding the structure-
function relationship of IncA and interactions with itself and SNAREs in order to design intracellular delivery
systems that can avoid lysosomal degradation. Distinct from our research with Opa and IncA, we have begun
to investigate potential antibiotic targets to help combat the increase in resistant bacteria. The signal peptidase
II, LspA, is a potential target because it is found in all Gram-negative bacteria and not humans. Globomycin
was isolated and the antibiotic activity was identified in 1978. Although the synthesis and structure are now
known, globomycin has not become a therapeutic. We aim to explore the binding and inhibition of LspA with
globomycin-like peptides in order to identify viable antibiotics for Gram-negative bacteria. The results of this
proposal with provide unique knowledge and insights about bacterial membrane proteins and their roles in
pathogenesis using biophysical approaches and will develop strategies for the design of therapeutics to treat
bacterial infections and a variety of human cancers involving CEACAM receptors.

## Key facts

- **NIH application ID:** 9920747
- **Project number:** 5R35GM131829-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Linda M Columbus
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,538
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9920747

## Citation

> US National Institutes of Health, RePORTER application 9920747, Biophysical understanding of pathogen-host membrane protein interactions for drug discovery and delivery (5R35GM131829-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9920747. Licensed CC0.

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