# Chemical Methods for Ferrous Iron Dependent Drug Delivery

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $536,653

## Abstract

Abstract
The emergence of multi-drug resistant Gram-negative pathogens (especially Pseudomonas aeruginosa,
Klebsiella pneumoniae, Acinetobacter baumannii, and the Enterobacteriaceae) represents the most serious
challenge faced by infectious disease clinicians today. This situation highlights the urgent need for new
therapeutics and innovative new therapeutic approaches to successfully treat these infections.
In the initial period of this R01 project, we developed a novel small-molecule approach for the Fe2+-dependent
delivery of diverse drug (or reporter) payloads. This platform has now been well validated in cells and in mouse
models of malaria and cancer. In the next period of the project, we will apply and optimize this strategy to
target important Gm-negative “ESKAPE” pathogens. Our hypothesis is that host-pathogen interactions
resulting from competition for iron resources present multiple opportunities for intervention with Fe2+-targeted
antibiotics. The various iron acquisition strategies employed by P. aeruginosa alone predict for targetable
pools of labile Fe2+ in the extracellular, periplasmic, and cytoplasmic compartments, depending on disease
state and site of infection.
Our research plan calls for the synthesis of Fe2+-targeted antibiotic conjugates designed to passively (Aim 1) or
actively (via siderophore-mediated uptake; Aim 2), transit Gm-negative membranes, and release compartment-
appropriate antibiotic payloads following reaction with Fe2+. To study and verify their modes of transport and
activation, we will employ non-Fe2+ reactive control conjugates, and a carefully selected panel of wild-type and
mutant strains with altered permeability, efflux pump/porin expression, or siderophore/transporter expression.
Susceptibility (MIC) testing will be performed under iron depleted and iron replete conditions using disease-
relevant, context specific, iron sources to mimic the microenvironment of the host-pathogen interaction around
iron. The most effective conjugates will be evaluated against a panel of Gm-negative clinical isolates obtained
from diverse infection sites and disease states. These studies will provide new insights into the iron acquisition
pathways of Gm-negative bacteria, and will inform the selection of promising leads for further study in murine
infection models. Finally, to exploit the extracellular Fe2+ produced during P. aeruginosa biofilm formation, we
will synthesize and characterize the first Fe2+-sensitive “smart” materials (Aim 3). Used as coatings on
indwelling devices, these novel materials would detect biofilm formation in situ and deliver antibiotics exactly
where and when they are needed. In summary, this project will apply the insights and chemical strategies
developed during the initial R01 period to a new therapeutic area, with the aim of introducing several new
innovations to the field of antibacterial therapy.

## Key facts

- **NIH application ID:** 9987486
- **Project number:** 5R01AI105106-08
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Adam R Renslo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $536,653
- **Award type:** 5
- **Project period:** 2013-05-29 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987486

## Citation

> US National Institutes of Health, RePORTER application 9987486, Chemical Methods for Ferrous Iron Dependent Drug Delivery (5R01AI105106-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9987486. Licensed CC0.

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