Scientists at the University of Washington Medicine in Seattle have engineered a new drug that can turn lung immune cells into slow-release antibiotic dispensers that eradicate deadly pneumonia infections in mice.
The promising treatment was described in the paper, “An Alveolar Macrophage-Targeted Ciprofloxacin Polymeric Prodrug Improves Survival in a Murine Model of Klebsiella Pneumoniae Pneumonia,” published in the journal, Antimicrobial Agents and Chemotherapy.
According to first author Ciana L. López, PhD, the innovative approach could help existing antibiotics dispel difficult-to-treat infections more effectively and with fewer side effects. Dr. López completed her doctoral studies at the University of Washington’s Department of Bioengineering in Seattle and is now a postdoctoral researcher at Duke University in Durham, North Carolina.
“We used a standard antibiotic, but by changing how it is delivered, we were able to significantly improve clearance of bacteria from the lungs, reduce inflammation and prolong survival with a single dose,” Dr. López said in a university news release.
The research team developed a compound known as a prodrug, an inactive form of a drug that only activates after the body metabolizes it. Prodrugs can extend drug half-life, ease storage and delivery and target specific cells or tissues. The group created this specific prodrug to gradually release medicine inside alveolar macrophages.
“We had seen that the antibiotic stays within cells for an extended period of time, suggesting the macrophages might serve as a reservoir from which the antibiotic would leak out into the surrounding tissue,” said Shawn J. Skerrett, MD, professor in the UW School of Medicine’s division of pulmonary, critical care and sleep medicine.
The prodrug resembles a molecular framework with chemical links attached to the antibiotic ciprofloxacin. It also included mannose sugars that mimicked those found on bacterial surfaces — a trick that propelled the alveolar macrophages to absorb the prodrug, mistaking it for a microbe. Once inside, the molecule unfastened the chemical links and released the antibiotic.
The UW team tested the efficacy of the prodrug by infecting mice with a fatal dose of Klebsiella pneumoniae — a hard-to-treat and increasingly drug-resistant bacterium. After 24 hours of the infection taking hold, researchers dispensed a single dose of the prodrug within a mist to one group of mice, while the other groups received ciprofloxacin alone, an inactive carrier molecule or a salt solution. They observed that the prodrug cleared the infection while the alternative administrations did not.
“The development of new antibiotics has stagnated over the past 50 years, so there’s a critical need to improve the delivery of existing drugs,” said senior author Patrick Stayton, PhD, UW professor of bioengineering. “Direct pulmonary delivery of targeted prodrugs for resistant infections like Klebsiella could provide a solution.”
