# Metagenomic discovery and optimization of novel endolysins targeting Cutibacterium acnes to treat acne vulgaris

> **NIH NIH R43** · TOPAZ BIOSCIENCES, INC. · 2023 · $275,250

## Abstract

PROJECT SUMMARY
Acne vulgaris (acne) affects up to 50 million people in the U.S. annually and can have significant negative
consequences on psychosocial functioning including higher rates of anxiety, low self-esteem, depression, and
suicidal ideation. Cutibacterium acnes plays a central role in acne pathogenesis and it is now understood that a
decrease in C. acnes phylotype diversity and an increase in the homogeneity of the pathogenic phylotype IA1
triggers innate immune stimulation and acne progression. Topical and oral antibiotics to target C. acnes remain
part of first-line treatments for acne, but continued use of antibiotics poses significant challenges including
exacerbation of antibiotic resistance as well as collateral damage to the healthy commensals in the gut and
skin microbiomes. Given these drawbacks, novel antimicrobial agents that can provide alternatives to
antibiotics and selectively target C. acnes without damaging beneficial bacteria are needed.
Endolysins are phage-encoded enzymes that can degrade bacterial cell walls. Exogenously added endolysins
can quickly lyse their target bacteria and because they bind very specific epitopes in target cell walls, they can
have lytic specificity down to a single species or even sub-species. Given these properties, endolysins hold
enormous potential as high-specificity skin microbiome modulators. However, the diversity of endolysins
known to target C. acnes is low and these enzymes suffer from low activity and low solubility. Recent
metagenomic analyses demonstrate that Cutibacterium sp. are found ubiquitously in the soil and that these
environments can provide a rich, untapped source of Cutibacterium diversity.
At Topaz Biosciences, we have developed a proprietary metagenomic platform for the discovery and
optimization of endolysins. We have previously leveraged this platform to develop endolysins against
Staphylococcus aureus that are more active, more thermostable, and have a broader pH range than
benchmark enzymes. In this Phase I proposal, we will leverage this platform to expand the diversity of
endolysins known to have activity against C. acnes and then exploit this diversity to develop chimeric
enzymes with improved properties. To accomplish this, we will take advantage of the modularity of
endolysins to build a library of endolysin “parts” – enzymatic domains (EADs) and cell wall binding domains
(CBDs) that we will systemically characterize for anti-Cutibacterium activity, thermostability, and pH tolerance.
An initial set of “parts” will come from sequenced Cutibacterium genomes and phages. Then, to significantly
expand the diversity of EADs and CBDs, we will computationally select ~200 diverse endolysins/domains
predicted to have anti-Cutibacterium activity from proprietary and public metagenomic databases for additional
characterization. Finally, we will leverage sequence-function insights gained from our “parts” development to
design chimeric endolysins composed of EADs and CBD...

## Key facts

- **NIH application ID:** 10821291
- **Project number:** 1R43AR082722-01A1
- **Recipient organization:** TOPAZ BIOSCIENCES, INC.
- **Principal Investigator:** Oliver Wei Liu
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $275,250
- **Award type:** 1
- **Project period:** 2023-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10821291

## Citation

> US National Institutes of Health, RePORTER application 10821291, Metagenomic discovery and optimization of novel endolysins targeting Cutibacterium acnes to treat acne vulgaris (1R43AR082722-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10821291. Licensed CC0.

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