# Combating Deadly Gram-negative Lung Infections: An Inhalation and Systems Approach

> **NIH NIH R01** · PURDUE UNIVERSITY · 2020 · $573,080

## Abstract

The Centers for Disease Control and Prevention (CDC) has recently escalated the antibiotic resistance threat
level in the USA with the Gram-negative ‘superbugs’ Pseudomonas aeruginosa, Klebsiella pneumoniae, and
Acinetobacter baumannii as being Serious to Urgent. Lung infections caused by bacterial ‘superbugs’
represent a major global health and economic burden. Due to the dry antibiotic discovery pipeline, polymyxins
are used as a last-resort against Gram-negative lung infections; however, parenteral polymyxins are
suboptimal due to very limited access of the drug to the infection site in the lungs. Simply increasing the
polymyxin dose is not an option because of the dose-limiting nephrotoxicity. Alarmingly, polymyxin
monotherapy can cause development of resistance. Pulmonary delivery of synergistic polymyxin combinations
holds a great promise with significant pharmacokinetic/pharmacodynamic/toxicodynamic advantages for
treating multidrug-resistant (MDR) lung infections. Unfortunately, traditional inhaled formulations have low
delivery efficiency; even worse, current inhaled polymyxin therapies are empirical and have never been
systematically optimized. Hence, safety, efficacy and patient compliance of inhaled polymyxin therapies are
significantly compromised. Excitingly, we have identified several polymyxin combinations which can completely
eradicate pandrug-resistant Gram-negatives without any regrowth. Our overarching hypothesis is that the
pulmonary delivery of optimized polymyxin combinations via novel powder aerosol formulations has negligible
toxicity, superior efficacy (compared to the clinically used nebulized CMS) and minimized resistance against
MDR Gram-negative lung infections. The Specific Aims are: (1) To optimize synergistic polymyxin
combinations for inhalation against lung infections caused by Gram-negative ‘superbugs’; (2) To develop novel
inhaled powder formulations using innovative particle engineering techniques; (3) To investigate the disposition
of polymyxins in the lungs with and without other antibiotics, and examine potential pulmonary adverse effects
using systems pharmacology; (4) To optimize dosage regimens for inhaled polymyxins and their combinations
based on the PK/PD in animal lung infection models. We must develop novel therapies to prevent bacteria
from outsmarting antibiotics and developing resistance. As no new antibiotic will be available for the MDR
Gram-negative pathogens in the near future, the NIAID has highlighted rational applications of ‘old’
antibiotics through combination therapy as a practical, swift and economical strategy. Our innovative
multi-disciplinary project will employ cutting-edge pharmaceutical engineering, molecular imaging and systems
pharmacology to generate urgently needed information for the optimal use of inhaled polymyxins and
combinations in patients. Importantly, our project responds in a timely manner to the National Plan for
Combating Antibiotic-resistant Bacteria.

## Key facts

- **NIH application ID:** 9980288
- **Project number:** 5R01AI132681-04
- **Recipient organization:** PURDUE UNIVERSITY
- **Principal Investigator:** Jian Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $573,080
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980288

## Citation

> US National Institutes of Health, RePORTER application 9980288, Combating Deadly Gram-negative Lung Infections: An Inhalation and Systems Approach (5R01AI132681-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9980288. Licensed CC0.

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