# Discovery and characterization of new bacterial cell wall targets and inhibitors to treat resistant infections

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2020 · $767,231

## Abstract

Project Summary
Antibiotic-resistant bacterial infections pose a substantial and growing threat to human health. There is a
pressing need to characterize new antibacterial targets and to develop methods that enable discovery and
characterization of inhibitors for these targets. The research described here focuses on understanding late
steps in the assembly of the peptidoglycan cell wall that surrounds bacterial cells. The cell wall is essential for
bacterial survival, making it an outstanding target for antibiotics. Indeed, some of the most important antibiotics
in history, the beta-lactams and the glycopeptides, target late steps in peptidoglycan assembly. Historically, the
enzymes that catalyze these late steps have been extremely difficult to study due to the nature of the
substrates that are required, the products that are formed, and the fact that many peptidoglycan biosynthetic
enzymes are polytopic membrane proteins or function only when complexed to a membrane protein. Recent
technological innovations made in our labs have advanced the field of peptidoglycan biosynthesis
considerably, and we are able to pursue challenging targets that have not previously been studied. This project
has four aims. Aim 1 involves further development of chemical tools to enable mechanistic and structural
studies of cell wall biosynthetic enzymes. Aim 2 focuses on understanding MurJ, the flippase that exports the
peptidoglycan precursor Lipid II from the cytoplasm to the cell surface where it is polymerized to produce
peptidoglycan. Aim 3 focuses on characterizing FtsW, the only universally conserved peptidoglycan
polymerase in bacteria. Aim 4 focuses on two novel Staphylococcus aureus cell wall hydrolase complexes that
process uncrosslinked peptidoglycan before it is integrated into the cell wall. These four aims will provide
fundamental information on how the bacterial cell wall is built. The studies will also provide new chemical tools,
assays, and scientific knowledge to enable the discovery of inhibitors that may be useful for treating resistant
bacterial infections.

## Key facts

- **NIH application ID:** 9860294
- **Project number:** 1R01AI148752-01
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Daniel Kahne
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $767,231
- **Award type:** 1
- **Project period:** 2020-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9860294

## Citation

> US National Institutes of Health, RePORTER application 9860294, Discovery and characterization of new bacterial cell wall targets and inhibitors to treat resistant infections (1R01AI148752-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9860294. Licensed CC0.

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