# Identifying Synergistic Rifabutin-Containing Combinations Against A. baumannii

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2024 · $688,572

## Abstract

PROJECT SUMMARY/ABSTRACT
 We have recently identified that rifabutin (RBT) is hyper potent against A. baumannii and we have
described this unique mechanism of action. We have characterized the mechanism for the hyperactivity and
found that RBT hijacks the A. baumannii iron transport protein FhuE, resulting in a Trojan horse-like, active
accumulation in the bacterial cell. However, FhuE expression is suppressed in the presence of rich media,
containing a high amount of free iron, and is expressed only in nutrient depleted conditions (e.g., RPMI-1640
media and in vivo), explaining why RBT has been previously overlooked. There is clinical interest in the
translation of RBT for A. baumannii therapy and BV100 (RBT IV formulation) is currently being studied in a
phase I clinical trial (NCT04636983) and phase II clinical trial (NCT05685615).
 However, significant barriers remain for the adoption of RBT as a treatment for A. baumanniii
infections. The goal of this proposal is to further support clinical translation through the rigorous testing of a
broad panel of clinical isolates, to develop a preclinical mouse model to model key RBT humanized
pharmacokinetics (PK) parameters to support defining MIC breakpoints, and to establish a high-throughput
RBT susceptibility testing protocol with low iron media that can be adopted by clinical labs according to CLSI
standards.
 Specific Aim 1: Develop and validate a RBT susceptibility testing method according to
CLSI standards. A) Head-to-head comparison of disc diffusion, or iron-depleted MHII and RPMI-1640
broth microdilution for RBT susceptibility testing across independent testing sites. B) Validate quality control
(QC) strains for RBT susceptibility testing across independent testing sites. C) Using our optimized testing
method, determine MICs for 250 international A. baumannii clinical isolates.
 Specific Aim 2: Characterize RBT-antibiotic drug combinations in vitro to identify
synergy and antagonism. A) Determine RBT-antibiotic interactions for antibiotics using a checkerboard
assay. B) Determine bacterial killing and frequency of resistance emergence using a hollow fiber infection
model.
 Specific Aim 3: Characterize RBT-containing therapeutic combinations in murine blood
and lung infection models. A) Determine if RBT-containing antibiotic combinations show in vivo synergy
when measuring CFUs as an endpoint in murine blood and lung infection models. B) Determine if
RBT-containing antibiotic combinations show in vivo synergy when measuring time to moribund condition as
an endpoint in murine blood and lung infection models.

## Key facts

- **NIH application ID:** 10877580
- **Project number:** 1R01AI179046-01A1
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Brian Michael Luna
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $688,572
- **Award type:** 1
- **Project period:** 2024-03-11 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877580

## Citation

> US National Institutes of Health, RePORTER application 10877580, Identifying Synergistic Rifabutin-Containing Combinations Against A. baumannii (1R01AI179046-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10877580. Licensed CC0.

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