# Advancing innovative therapies against pandrug-resistant Gram-negative superbugs

> **NIH NIH R01** · PURDUE UNIVERSITY · 2021 · $646,174

## Abstract

The World Health Organization (WHO) has recently listed Gram-negative ‘superbugs’ Klebsiella pneumoniae,
Pseudomonas aeruginosa, and Acinetobacter baumannii as the most critical pathogens, which are the greatest
threat to human health. Due to the slow progress in development of novel antibiotics, polymyxins are often used
as the last-line therapy against Gram-negative infections; however, clinical studies have shown that the efficacy
of parenteral polymyxins is disappointing for the treatment of Gram-negative lung infections due to very low
exposure of the drug to the infection site at the airway surface and dose-limiting kidney toxicity. More worrying
is the development of polymyxin resistance induced by the polymyxin monotherapy. One of the promising
strategies for the treatment of Gram-negative lung infections is direct delivery of synergistic polymyxin
combinations to the infection sites at the airway surface. However, conventional nebulization has low delivery
efficiency; even worse, current colistin methanesulfonate (CMS) nebulization therapies are empirical and have
never been systematically optimized using pharmacokinetic/pharmacodynamic/toxicodynamic (PK/PD/TD).
The overall aim of this project is to develop novel liposomal therapies for combinational antibiotics using
innovative spray-freeze-drying powder production technology, cutting-edge imaging, systems pharmacology and
mechanism-based pharmacokinetic/pharmacodynamic/toxicodynamic (PK/PD/TD) modeling. The Specific
Aims are: (1) to develop novel liposomal formulations of polymyxin combinations using innovative spray-freeze-
drying technology; (2) to determine in vitro pharmacodynamics of the formulations; (3) to elucidate the disposition
of polymyxin combinations from the formulations in the airway using cutting-edge imaging and the mechanisms
of potential pulmonary toxicities using systems pharmacology; (4) to apply mechanism-based PK/PD/TD
modeling to optimizing dosage regimens of the superior liposomal formulation in rodent lung infection models.
To combat the emergent global antimicrobial crisis, we must outpace the evolution of ‘superbugs’ by novel
strategies. With the disappointing progress in developing new antibiotic against MDR Gram-negative pathogens,
our innovative multi-disciplinary project addresses NIAID’s strategic approach “extending the clinical
utility of antibacterial drugs̸optimizing use of existing drugs and combination therapies to suppress
emergence of resistance and minimize toxicity”. The success of our work will have a broader impact to the
USA and global health as the platform can be readily applied to develop superior new therapies for other
respiratory infections such as pulmonary tuberculosis.

## Key facts

- **NIH application ID:** 10189507
- **Project number:** 5R01AI146160-03
- **Recipient organization:** PURDUE UNIVERSITY
- **Principal Investigator:** Jian Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $646,174
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10189507

## Citation

> US National Institutes of Health, RePORTER application 10189507, Advancing innovative therapies against pandrug-resistant Gram-negative superbugs (5R01AI146160-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10189507. Licensed CC0.

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