# Molecular Mechanism of an Exporter-like ABC Importer YbtPQ

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $499,200

## Abstract

Bacterial infections pose one of the most significant global public health challenges, exacerbated by the
emergence of antibiotic-resistant strains. As a result, treating these infections has become increasingly difficult.
Recently, the FDA approved cefiderocol, a siderophore-antibiotic conjugate, as a new treatment for urinary tract
infections (UTIs) caused by antibiotic-resistant Gram-negative bacteria. This approval highlights the potential of
targeting the bacterial siderophore-mediated metal uptake process for pharmaceutical interventions. A crucial
step in this process involves the uptake of metal-chelated siderophores across the bacterial inner membrane,
facilitated by ATP-binding cassette (ABC) importers. Unfortunately, the detailed molecular mechanisms
underlying these importers remains poorly understood, impeding the development of targeted drugs. This
proposal focuses on a unique example of these critical importers: the yersiniabactin importer YbtPQ from
uropathogenic E. coli, the leading cause of UTIs. Our preliminary studies have revealed that YbtPQ exhibits
folding characteristics similar to an ABC exporter, representing a novel type of ABC transporter. Building upon
this discovery, we expect to study the fundamental structure-function relationship of YbtPQ by pursuing two
specific aims: 1) Define the substrate selectivity and inhibitory mechanism of YbtPQ; 2) Understand the unique
structural motifs within YbtPQ. To accomplish these goals, we will employ a multidisciplinary approach,
combining mutagenesis, specifically-designed transport assays, microscale thermophoresis, circular dichroism,
native mass spectrometry, molecular dynamic simulations, and cryo-electron microscopy. Successful completion
of this proposal will yield valuable insights into the substrate/inhibitor selectivity and transport dynamics of YbtPQ.
This knowledge will serve as a solid foundation for future drug development targeting this importer, offering new
possibilities for effectively treating bacterial infections and addressing the challenges of antibiotic resistance.

## Key facts

- **NIH application ID:** 10877484
- **Project number:** 1R01AI177445-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Hongjin Zheng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $499,200
- **Award type:** 1
- **Project period:** 2024-07-17 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877484

## Citation

> US National Institutes of Health, RePORTER application 10877484, Molecular Mechanism of an Exporter-like ABC Importer YbtPQ (1R01AI177445-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10877484. Licensed CC0.

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