# Bacterial Cell Wall Composition and the Influence of Antibiotics

> **NIH NIH R01** · STANFORD UNIVERSITY · 2022 · $331,888

## Abstract

PROJECT SUMMARY
The emergence of resistance to almost every antibiotic underscores the urgent need to introduce new
therapeutics and to understand antibiotic modes of action to help guide the development of new antimicrobials
effective against drug-resistant organisms. S. aureus together with Enterobacter species, Klebsiella
pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterococcus faecium, are categorized
as the ESKAPE pathogens and are predominant causes of hospital-acquired infection worldwide. Among
these, methicillin-resistant Staphylococcus aureus is the leading cause of mortality from antibiotic-resistant
infections in the United States. Moreover, the propensity of these pathogens to form biofilms and persister cells
is linked to recurrent and chronic infections leading to pneumonia, endocarditis, bacteremia, and sepsis.
Biofilms consist of slow-growing bacterial cells surrounded by a protective extracellular matrix, while persister
cells are dormant, highly antibiotic-tolerant bacteria that can persist in the host. Worldwide, tuberculosis is the
second most common cause of death, following deaths from HIV/AIDS, and is caused by Mycobacterium
tuberculosis. In the U.S., respiratory infections from non-tuberculosis mycobacteria (NTM) are increasing,
notably prevalent among CF patients and individuals suffering from chronic lung disease. The treatment for
NTM is complex, similar to that for TB, and requires prolonged combination drug therapy as monotherapy is
highly associated with drug resistance. We have initiated an antibiotic discovery and mode-of-action activity
program directed at the development of new therapeutics for these serious infectious diseases. In this
proposed project, we leverage our recent success in designing a new vancomycin derivative, a vancomycin-D-
octaarginine (V-r8) conjugate, that eradicates Gram-positive biofilm and persister cells and reduces
pathogenesis in vivo. We propose to uncover new discoveries regarding V-r8’s unique mode of action, as
compared to major high-value therapeutics that are now the drugs of last resort, e.g. oritavancin, towards its
development and clinical potential and to inspire the generation of new antibacterial agents. The research
design integrates interdisciplinary chemical and biochemical expertise and perspectives; mechanistic
biochemistry; and integration of solid-state NMR approaches to measure compositional changes in whole cells
and to determine distances between V-r8 and possible multiple binding sites. Furthermore, we will launch a
new experimental solid-state NMR platform to enable us to evaluate drug modes of action in mycobacteria.
This platform will be broadly applicable to investigations of complex mycobacterial cell walls and will be
specifically directed here to interrogate the activity of CPZEN-45, an exciting therapeutic candidate for the
treatment of both Mycobacterium tuberculosis and NTM.

## Key facts

- **NIH application ID:** 10401466
- **Project number:** 5R01GM117278-07
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Lynette S Cegelski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $331,888
- **Award type:** 5
- **Project period:** 2016-09-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10401466

## Citation

> US National Institutes of Health, RePORTER application 10401466, Bacterial Cell Wall Composition and the Influence of Antibiotics (5R01GM117278-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10401466. Licensed CC0.

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