Cystic fibrosis (CF) disease leads to complex lung infections due to the buildup of mucus in the airways. However, the CF infectious landscape has changed since the 2019 approval of a new therapy called Elexacaftor/Tezacaftor/Ivacaftor (ETI). ETI is not an antibiotic; it targets the underlying cause of CF. The drugs have improved lung function, reduced sputum production, and lowered pathogen load in people with CF (pwCF). However, recent literature shows that airway infections caused by Pseudomonas aeruginosa, Staphylococcus aureus, and others persist despite symptom improvements. ETI’s success has created a microbiological paradox: infection persists, but the reduction in sputum production makes studying them more difficult. New evidence suggests that ETI alters mucus biochemistry, most notably, amino acid concentrations. Yet the ecological and functional consequences of these shifts on the CF lung microbiome remain unexplored and it is now more difficult to study them without sputum.
Experiments using a Synthetic Bacterial Community (SBC) under nutrient depleted conditions were conducted to mimic the effects of ETI on the microbial niche spaces within CF mucus. Surprisingly, our nutrient depletions had little effect on microbiome structure; instead, it was found that the nutrient depletions altered the community physiology, seen through changes in nitrite concentrations, total bacterial load, and media pH. One of the more interesting findings was alterations of the SBC metabolome under lower amino acid concentrations, specifically the reduction in small molecule virulence factors produced by P. aeruginosa. These effects were further investigated by performing microbial competition assays in low amino acid conditions and it was found that P. aeruginosa was less competitive under low amino acids. This also reduced its virulence in human cell toxicity assays.
This study demonstrates that indirect effects of the powerful modulator drugs ETI can significantly impact microbial physiology without altering community composition. These findings suggest that ETI may have hidden benefits to pwCF via modulating pathogen behavior due to altered biochemical mucus conditions. The results foreshadow what the future of CF lung infections may look like when most pwCF are on ETI for longer periods.
Read the full journal article titled ‘Microenvironmental Effects of a Non-Antibiotic Therapy for a Chronic Polymicrobial Infection Alter Microbial Physiology, Competition, and Virulence‘ in The ISME Journal. This article has been selected as Editor’s Choice for the month of June 2025.
Authors
- Cely T. González, Michigan State University, US
- Christian Martin, Michigan State University, US
- Maddey Crane, Michigan State University, US
- Karen Gutierrez, Michigan State University, US
- Jacob Thomas, Michigan State University, US
- Lacy Remisoski, Michigan State University, US
- Maxwell Okros, Michigan State University, US
- Dustin Finkhouse, Michigan State University, US
- Yousi Fu, Michigan State University, US
- Douglas V. Guzior, Michigan State University, US
- Jenna Mielke, University of California San Diego, US
- Gabriel Querido, University of California San Diego, US
- Lienwil Padillo, University of California San Diego, US
- Reda Girgis, Corewell Health, MI, US
- Marc McClelland4, Corewell Health, MI, US
- Douglas Conrad, University of California San Diego, US
- Xiaopeng Li, Michigan State University, US
- Robert A. Quinn, Michigan State University, US