![[Translate to English:] 3D-kontrastierte Oberflächenstruktur von LasB (beige) mit einem Inhibitor der 3. Generation (dunkelblau), der Zink (grau) bindet.](/fileadmin/_processed_/8/b/csm_LasB_Foto_b7734ae7a4.png)
Pseudomonas aeruginosa is a cunning opponent. Like many bacterial pathogens, it rapidly develops resistance to antibiotics. As one of the most prevalent hospital-acquired infections, it can cause pneumonia, urinary tract infections, and severe eye conditions that may lead to complete blindness if the cornea is damaged.
A key driver of this corneal destruction is an enzyme called elastase, or LasB for short. "LasB essentially 'clears the way' for the bacterium," explains Dr. Jörg Haupenthal, a scientist in the team of Professor Anna Hirsch, head of the department “Drug Design and Optimization” at HIPS. Haupenthal is leading a project focused on developing new treatments for P. aeruginosa.
LasB facilitates the spread of P. aeruginosa by breaking down large proteins like collagen and disrupting critical immune system components. If the bacterium and its enzyme reach the eye, the cornea, which is predominantly composed of collagen, is at high risk of developing infectious keratitis. P. aeruginosa and LasB are responsible for a significant proportion of the 1.5 million keratitis-related blindness cases each year.
Dr. Alexander Kiefer, a chemist and co-lead author of the Advanced Science study alongside Dr. Christian Schütz, elaborates on their strategy. "LasB contains a zinc complex, and we have effectively chelated it," Kiefer explains. In other words, they designed a peptide inhibitor that binds to two specific sites on the enzyme's zinc complex, rendering LasB completely harmless. This prevents the degradation of crucial proteins like collagen and protects immune system components from attack. Importantly, the inhibitor selectively targets LasB without affecting essential metal-containing enzymes in healthy human tissue. Kiefer will start the junior research group “Antimicrobials through Chemoenzymatic Synthesis” at HIPS in April.
Unlike conventional antibiotics, the LasB inhibitor has so far shown no signs of triggering bacterial resistance. "By neutralizing LasB rather than killing the bacterium outright, we deprive P. aeruginosa of its pathogenic properties, giving it no evolutionary pressure to develop resistance," Kiefer explains. Additionally, unlike many antibiotics, the inhibitor does not disrupt the gut microbiome.
While the development of an actual drug is still uncertain, further studies are planned. "Our clear goal is to develop a viable therapeutic based on this research," says Anna Hirsch, who coordinates the project as the corresponding author. As the designated spokesperson for the planned nextAID³ Cluster of Excellence, Hirsch emphasizes the broader impact of their work. "Interdisciplinary research like this, involving multiple experts across different faculties, is key to developing new treatments for a range of diseases beyond infections. With the help of artificial intelligence, nextAID³ aims to accelerate the translation of fundamental research into clinical applications."
