# Cell Surface Polymer Display in Gram-Positive Bacteria

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $579,607

## Abstract

Project Summary
Gram-positive bacteria are surrounded by a thick peptidoglycan cell wall that is covalently affixed with a diverse
array of macromolecules that maintain cell integrity and promote effective interactions with the environment. In
clinically important bacterial pathogens, these macromolecules function as essential virulence factors. Our
research will investigate how bacteria elaborate their surfaces with adhesive pili and cell wall glycopolymers that
are critically important for microbial pathogenicity and growth. Both are attached to the same site on the cell
surface and their relative abundance is balanced to maintain homeostasis. We will study the prototypical SpaA-
pilus from Corynebacterium diphtheriae, the causative agent of the severe respiratory disease, diphtheria. The
SpaA-pilus and related pili in >1,800 bacterial species are assembled by polymerases that covalently link pilus
protein subunits (pilins) via lysine-isopeptide bonds that confer enormous tensile strength. By synergistically
employing structural, biochemical, cellular, computational, and proteomic methods, we aim to learn how these
polymerases select and crosslink their pilin substrates to build pili. We will also determine the first-ever atomic
level structure of a crosslinked pilus and uncover the full array of pilus structures that inhabit the surface of C.
diphtheriae. In complementary studies, we seek to identify small molecules that selectively disrupt the synthesis
of glycopolymers that coexist with pili on the cell surface. Using a newly developed cell-based assay we will
screen for compounds that inhibit the synthesis of an important cell wall glycopolymer in methicillin-resistant
Staphylococcus aureus (MRSA). These inhibitors have the potential to be developed into novel therapeutics as
they would impair MRSA's ability to cause infections and re-sensitize it to existing β-lactam antibiotics.
Combined, our comprehensive studies of pilus and cell wall glycopolymer biogenesis will provide fundamental
insight into the chemistry underlying polymer assembly on the surface of gram-positive bacteria and could lead
to new antibiotics to treat infections caused by MRSA and other drug-resistant bacteria.

## Key facts

- **NIH application ID:** 10980973
- **Project number:** 2R01AI052217-20A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Robert Thompson Clubb
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $579,607
- **Award type:** 2
- **Project period:** 2002-06-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10980973

## Citation

> US National Institutes of Health, RePORTER application 10980973, Cell Surface Polymer Display in Gram-Positive Bacteria (2R01AI052217-20A1). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10980973. Licensed CC0.

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