New Weakness Identified in Common Hospital Bacterium

Comparison of P. aeruginosa wild type (left) and protease deletion strain (right): effects on cell shape, biofilm formation, and antibiotic resistance. Picture: DESY

Pseudomonas aeruginosa is among the most resilient pathogens in medicine, known for its resistance to numerous antibiotics, its ability to form protective biofilms, and its survival under extreme stress. However, researchers at the Centre for Structural Systems Biology (CSSB) on the DESY campus, working with colleagues from the UK and the U.S., have identified a promising weakness. The international team has discovered three enzymes that regulate crucial processes related to stress resistance and biofilm formation. These enzymes could serve as future drug targets, offering a potential new strategy to combat multidrug-resistant infections.

Pseudomonas aeruginosa is part of the ESKAPE group—a cluster of pathogens notorious for causing hospital-acquired infections and exhibiting strong antibiotic resistance. This bacterium is known to trigger pneumonia, urinary tract infections, and sepsis, particularly in individuals with weakened immune systems or chronic conditions like cystic fibrosis. One of its most dangerous traits is its capacity to form biofilms on surfaces such as catheters and implants. These slimy layers shield the bacteria, significantly increasing their resistance to treatment.

Successfully knocked out

The research team, led by Holger Sondermann and María Jesús García-García, focused on three genes in Pseudomonas aeruginosa whose functions had not been previously identified. “The bacterium has between 5,000 and 6,000 genes,” says Sondermann, “but we only understand what about two-thirds of them do.” To investigate further, the team selectively deactivated the genes in question and observed noticeable effects: the modified strains could not grow under osmotic stress, produced weaker biofilms, and showed increased vulnerability to commonly used antibiotics.

However, disabling just one of the genes wasn't enough to significantly affect the bacterium. Only when all three genes were simultaneously deactivated did the changes in behavior become clear. “The enzymes in Pseudomonas are redundant,” García-García explains. “They can compensate for one another, so removing only one doesn’t make a noticeable difference.”

The researchers also determined the three-dimensional structure of the enzymes using X-ray crystallography and found a surprising similarity: their structure closely resembles that of HIV protease, a critical enzyme targeted in AIDS treatment. “This was unexpected,” says Sondermann. “We discovered that bacteria possess enzymes structurally similar to HIV protease.” Despite the structural resemblance, their functions differ. While HIV protease processes long protein chains into functional segments to enable viral replication, the specific protein targets of the Pseudomonas enzymes are still unknown.

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Doubling the odds

The three identified enzymes show strong potential as targets for future medical treatments. Disabling them could increase Pseudomonas aeruginosa’s susceptibility to antibiotics it typically resists, while also weakening its ability to form robust biofilms—providing treatments with a significant edge. “It may not be necessary to develop entirely new antibiotics,” says María Jesús García-García. “We might be able to boost the effectiveness of existing ones by specifically blocking these enzymes.”

However, several questions still need to be addressed. Researchers have yet to determine which protein molecules these newly discovered proteases act on. Preliminary findings suggest they may cleave polyglutamate sequences, but it's unclear whether such sequences naturally occur in Pseudomonas or only emerge under certain stress conditions. “Our next step is to identify the enzymes' natural targets,” García-García explains. “Understanding their role in the bacterium is essential to ensure future therapies are safe and avoid unintended effects.”

The team also plans to begin testing potential enzyme inhibitors. Since these enzymes are present in harmful bacteria like Pseudomonas and Legionella—but are rarely found in beneficial gut microbes—targeted treatments could attack dangerous pathogens without disrupting the healthy microbiome. Despite the encouraging progress, the researchers remain grounded. “Creating new medications takes time,” notes Holger Sondermann. “But we’re cautiously optimistic that these enzymes could offer a promising new therapeutic avenue—similar to how HIV protease became a breakthrough target in AIDS treatment.”