# Development of Antibiotic Adjuvants for Gram-Negative Bacteria

> **NIH NIH R01** · UNIVERSITY OF NOTRE DAME · 2022 · $720,934

## Abstract

Multi-drug resistant (MDR) Gram-negative bacterial infections present an enormous ongoing challenge to
public health. Colistin, a polymyxin antibiotic with noted renal toxicity, is now considered an antibiotic of last
resort for the treatment of these infections. With the resurgence in colistin use, colistin-resistant isolates are
now becoming more common, especially with the spread of the plasmid-borne mcr-1 gene. To combat the
growing threat of colistin-resistance, we initiated a research program to identify small molecules, termed
antibiotic adjuvants, that modulate the activity of colistin against MDR Gram-negative pathogens. We have
identified molecules that lower the minimum inhibitory concentration (MIC) of colistin up to 2048-fold against
both colistin-sensitive and colistin-resistant bacteria (Acinetobacter baumannii, Pseudomonas aeruginosa,
Klebsiella pneumoniae, and Escherichia coli). Mechanistic studies have shown that our lead compound binds
the response regulator PmrA in A. baumannii, downregulates the pmrCAB operon, and reverses lipid A
modification. As colistin toxicity is dose dependent, the potential of these compounds to lower dosages for the
treatment of MDR Gram-negative bacteria could thereby mitigate toxicity. In the case of colistin-resistant
bacteria, this approach would serve to suppress the MIC below the clinically defined breakpoint for resistance
and again render colistin therapy efficacious to treat infections for which otherwise there may be no effective
antibiotics.

## Key facts

- **NIH application ID:** 10468029
- **Project number:** 5R01AI136904-05
- **Recipient organization:** UNIVERSITY OF NOTRE DAME
- **Principal Investigator:** Christian Corey Melander
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $720,934
- **Award type:** 5
- **Project period:** 2018-09-21 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10468029

## Citation

> US National Institutes of Health, RePORTER application 10468029, Development of Antibiotic Adjuvants for Gram-Negative Bacteria (5R01AI136904-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10468029. Licensed CC0.

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