Pseudomonas aeruginosa is known to cause antibiotic-recalcitrant pneumonia and it is notoriously dangerous in people with lung diseases like cystic fibrosis, COPD, or bronchiectasis. P. aeruginosa forms biofilms—bacteria encased in a self-produced matrix that provides them with significant advantages, including protection from antibiotics. But biofilms come at a cost: the clustered bacteria also lose the ability to move around, find nutrients, and spread effectively. For P. aeruginosa infecting a lung, this poses a dilemma: should it spread across the lung’s surface or form a biofilm? The mechanisms driving the bacteria’s adaptation during human infections remain unclear.

Now, researchers have investigated P. aeruginosa growth and antibiotic tolerance in tissue-engineered airways by transposon insertion sequencing (Tn-seq). They uncovered how P. aeruginosa switches between biofilm formation for antibiotic protection and a planktonic state to spread and access nutrients, depending on the environmental pressures they face.

This work is published in Nature Microbiology in the paper, “Pseudomonas aeruginosa faces a fitness trade-off between mucosal colonization and antibiotic tolerance during airway infections.

To better understand P. aeruginosa’s behavior, researchers grew the bacteria on mucus-covered lung organoids. “We then used a high throughput screening technique called transposon-insertion sequencing (Tn-seq), combined with metabolic modeling and live imaging, to study how P. aeruginosa adapts to colonize the mucosal surface of the lung and tolerate antibiotic treatment,” said Lucas Meirelles, PhD, EMBO postdoctoral fellow at École Polytechnique Fédérale de Lausanne (EPFL).

The scientists identified which genes were important for the bacterium’s survival under different conditions: those that contributed to fitness during mucosal colonization and those that helped the bacteria tolerate antibiotics. They then used computational modeling to simulate how the bacteria metabolize nutrients in the lung environment, which helped pinpoint the exact metabolic pathways P. aeruginosa relies on during infection.

biofilm
A biofilm formed by two Pseudomonas aeruginosa strains (chronic-like in green, acute-like in orange) growing inside the airway epithelium (magenta). [Lucas Meirelles (EPFL)]

Metabolic modeling based on the Tn-seq data revealed the nutritional requirements for P. aeruginosa growth, highlighting a reliance on glucose and lactate and varying requirements for amino acid biosynthesis. This self-sufficiency, or “metabolic independence,” helps the bacterium thrive in the early stages of lung infection.

Further, the findings suggest that biofilm formation imposes a “metabolic burden,” slowing down the bacteria’s ability to spread. In experiments, bacteria that couldn’t form biofilms spread more efficiently but were left vulnerable to antibiotics. Tn-seq also revealed selection against biofilm formation during mucosal growth in the absence of antibiotics.

The authors noted, “Live imaging in engineered organoids showed that biofilm-dwelling cells remained sessile while colonizing the mucosal surface, limiting nutrient foraging and reduced growth. Conversely, biofilm formation increased antibiotic tolerance at the mucosal surface.”

The study highlights the delicate balancing act that P. aeruginosa must perform during infections. While the bacteria need to colonize the lung effectively, their best survival strategy (forming biofilms) limits their access to nutrients and, therefore, their ability to spread. However, once antibiotics are introduced, biofilm formation becomes advantageous, protecting the bacteria from being wiped out.

The discovery opens the door for the exploration of new treatment strategies. For example, disrupting the bacteria’s ability to form biofilms without giving them more room to spread could make them more vulnerable to existing treatments. And therapies that target the bacteria’s metabolic pathways may also prove to be effective at weakening Pseudomonas infections.

This study also made advances in studying antibiotic resistance. “Antibiotic resistance is set to become one of the most serious healthcare challenges of this century, and P. aeruginosa is a major contributor to this issue,” said Meirelles. “By using tissue engineering to replicate the airway environment in the lab, we aim to better understand the physiology of this pathogen. Our hope is that this will uncover previously unknown targets to help us combat these infections and address antibiotic resistance.”

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