Analysis uncovers molecular reasons for cystic fibrosis drug resistance microbiologystudy

Breathing—a natural and essential process—can be an incredibly labored process for people with cystic fibrosis. CF, a genetic disease that affects secreted fluids (mucus, sweat, digestive juices), causes problems throughout the body, but most CF patients have symptoms in the lungs.

Where mucus in the lungs is normally thin and slippery, the mucus of CF patients is thick and sticky, which clogs up the airways and makes breathing difficult, like having the worst seasonal allergies you’ve ever experienced but persisting through every moment of every day.

Although CF remains lethal, the disease burden and quality of life for many patients has increased thanks to revolutionary drugs that the U.S. Food and Drug Administration has approved in recent years.

However, even though these treatments all target CFTR, the ion channel that causes CF when it becomes mutated, not all CFTR variants respond well—or at all—to these drugs.

A recent study from the labs of Lars Plate and Jens Meiler, published in the Proceedings of the National Academy of Sciences, analyzed both selectively responsive and poorly responsive variants and revealed the molecular determinants of drug response. Plate and Meiler are faculty members in the College of Arts and Science and have associations with the School of Medicine Basic Sciences.

“This project used computational structural biology and experimental chemical biology approaches that I learned from the Meiler lab and Plate lab, respectively,” said Eli Fritz McDonald, the first author of the study.

“I had a unique opportunity to be co-advised by both Lars and Jens during my Ph.D. at Vanderbilt, and it afforded me the opportunity to leverage multiple levels of complexity to attack this research problem.”

McDonald, who graduated from the chemistry Ph.D. program last year, didn’t just happen onto this field of research, however. “My cousin, Analiese, suffered from cystic fibrosis and passed away at the young age of 20 during my graduate studies,” he said.

“Her battle with CF directly inspired and motivated this research, since the CFTR variants she had were untreatable at the time she passed.”

There are three types of CFTR mutations, one of which results in a protein that is unable to fold properly and results in limited or negligible CFTR function.

One of the FDA treatments approved for this type of mutation uses two of what is called a “corrector” drug, which interacts with the ion channel in a particular way that helps compensate for the folding error. Unfortunately, around 3% of CF patients, like Analiese, harbor “poorly responsive” variants and don’t improve with treatment.

In their PNAS paper, the authors describe how, even when different poorly responsive CFTR variants have mutations in the same regions, the resulting proteins are unstable to different degrees. This variability suggested to the authors that some proteins could be “corrected” more easily and could be convinced to respond to the FDA-approved therapeutics.

To test this idea, McDonald and team induced new mutations in the variants that compensated for the instability in each variant and found that many of the poorly responsive variants became responsive to the FDA-approved cocktail of corrector drugs.

According to the authors, developing new corrector drugs that target these poorly responsive CFTR variants is a promising approach to bringing the revolutionary treatments to more CF patients.

“In a perfect world, every patient would have drugs that they respond to,” Plate said. “Using a precision medicine approach, patients with CF could one day be paired with the drug combinations that best work for them and their variants.” Plate was selected as a 2025 Chancellor Faculty Fellow thanks in part to his expertise in protein folding and trafficking.

CF patients who are currently resistant to medication can look to the work that Plate and Meiler are doing in the hope that they might one day have access to a corrector drug that works for them (McDonald is now a postdoctoral fellow at St. Jude Children’s Hospital studying the molecular underpinnings of pediatric disease).

“We couldn’t have done it without federal funds from the National Heart, Lung, and Blood Institute and the National Institute of General Medical Sciences,” Plate said.

Plate is an associate professor of biological sciences and chemistry in the College of Arts and Science. Meiler is a distinguished research professor of chemistry. Plate and Meiler are members of the Vanderbilt Institute of Chemical Biology, and Meiler is a member of the Center for Structural Biology.