# Vibrio microcins. A hidden field of targeted anti-cholerae natural products.

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2024 · $766,056

## Abstract

Project Summary
Cholera is a deadly diarrheal disease caused by the bacterial pathogen Vibrio cholerae. It remains poorly
controlled in many parts of the world and outbreaks have been surging despite global efforts to reduce infection.
New antibacterials for Gram-negative bacteria like V. cholerae are greatly needed but are also the most
challenging to make because the outer membrane of these bacteria excludes nearly all molecules from entering
the cell. An innovative strategy to overcome this permeability barrier is shown by the new clinical antibiotic
cefiderocol, which binds outer membrane siderophore receptors and uses active transport systems to enter the
periplasm. Unfortunately, few molecules are known that are capable of this feat, and we have been largely limited
to using siderophore conjugates to develop these innovative Trojan horse antibiotics. Our work on the
understudied class of bacteriocins called microcins provides a rare opportunity to investigate a broader class of
antibacterials with this membrane translocation ability. Microcins are small antibacterial proteins (<10kDa) that
selectively bind Gram-negative outer membrane proteins and hijack active transport processes to enter the
periplasm. Microcins have are effective at controlling bacterial pathogen growth in vivo and have many
characteristics that could make them attractive antibiotic scaffolds. Despite their potential value, advances in
microcin biology have been impeded by the challenges of their identification and the limited characterization of
the only 15 known examples. To overcome the discovery bottleneck, we developed an approach for systematic
identification and validation of new microcins. Coupling an in silico pipeline with a new method for microcin
activity screening, we are identifying microcins across phylogenetically diverse bacteria, including phylogroups
that have never been examined for microcin activity, such as the Vibrionaceae. We have identified potent Vibrio
microcins active against all clinical strains of V. cholerae tested and which we show can be delivered by bacteria
vectors to reduce V. cholerae colonization in mice. Our new appreciation for class II microcin diversity and their
potential to treat V. cholerae infections has made plain the critical need to develop detailed knowledge of their
sequence-activity relationships and ability to prevent and treat gut infections using cell-based delivery vectors to
empower their use in antibiotic development. To pursue these critical gaps in knowledge, we will take advantage
of our exclusive repertoire of unrecognized V. cholerae class II microcins and will (Aim 1) provide the first in-
depth microcin sequence-activity study to uncover domains import for receptor binding, cell entry, and
antibacterial activity, (Aim 2) investigate the use of different delivery bacteria, dosing regime, and microcin
expression systems on microcin efficacy in mouse models, and (Aim 3) expand our understanding of the range
of...

## Key facts

- **NIH application ID:** 10859969
- **Project number:** 1R01AI182365-01
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Bryan William Davies
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $766,056
- **Award type:** 1
- **Project period:** 2024-06-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10859969

## Citation

> US National Institutes of Health, RePORTER application 10859969, Vibrio microcins. A hidden field of targeted anti-cholerae natural products. (1R01AI182365-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10859969. Licensed CC0.

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