# Diverted Total Synthesis and Biological Evaluation of Natural Product Biofilm Inhibitors, The Cahuitamycins

> **NIH NIH F32** · EMORY UNIVERSITY · 2020 · $48,071

## Abstract

Project Summary/Abstract
Multidrug resistant (MDR) Gram-negative bacteria represent a global health crisis. Traditional
antibiotics create selective pressure and breed resistance, making our current drugs less and less
effective. Targeting of bacterial virulence factors has gained interest as an alternative strategy to
potentially circumvent this problem. Virulent Acinetobacter baumannii rely on multiple virulence
mechanisms to establish infection, including biofilm formation and siderophore-mediated iron
acquisition. Biofilms are communities of bacteria bound together by extracellular matrices that
adhere to surfaces and display enhanced antibiotic resistance, and siderophores are small-
molecule chelators that scavenge life sustaining iron from host sources. Recently, a group of
natural products dubbed the cahuitamycins were structurally characterized and determined to
have biofilm-inhibitory activity against A. baumannii. The cahuitamycins contain bidentate
chelating motifs found ubiquitously in siderophore structures (phenolate-oxazoline and
hydroxamate); however, ring-opening of the oxazoline completely abolishes anti-biofilm activity.
This heavily implies that the siderophore-like nature of these molecules is closely related to their
mechanism of antibiotic activity. Herein, we propose to study the cahuitamycins to shed light on
the biochemical connection between these two clinically relevant virulence factors.
To this end, we propose two interrelated aims focusing respectively on the organic synthesis of
cahuitamycins and analogs thereof, and on the biological evaluation of the cahuitamycins and the
siderophore-biofilm relationship in A. baumannii. We have devised a synthetic route to the
cahuitamycins that is highly convergent for the rapid generation of diverse analog panels.
Derivatives will be tested for their ability to inhibit biofilm-formation, and the resulting structure-
activity relationships will be used to design functionalized cahuitamycin probe molecules. In
parallel, biofilm formation in A. baumannii will be evaluated using siderophore-deficient mutant
libraries, phenotypic profiling by confocal microscopy, and transcriptomic analysis of
cahuitamycin-treated A. baumannii. Use of Activity-based Protein Profiling will enable
cahuitamycin target identification, and computational docking will provide insight into mechanism
of action. This proposal integrates two cutting edge research areas in the field of infectious
disease, biofilm formation and siderophores, and as such is positioned to produce highly impactful
and foundational work for the future development of novel anti-virulence therapeutics.

## Key facts

- **NIH application ID:** 9986454
- **Project number:** 5F32GM133091-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Justin A. Shapiro
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $48,071
- **Award type:** 5
- **Project period:** 2019-07-17 → 2021-03-21

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986454

## Citation

> US National Institutes of Health, RePORTER application 9986454, Diverted Total Synthesis and Biological Evaluation of Natural Product Biofilm Inhibitors, The Cahuitamycins (5F32GM133091-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9986454. Licensed CC0.

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