Bacterial prostatitis, an infection of the prostate primarily caused by the bacterium Escherichia coli (E. coli), is a common health problem in men. About one percent of men worldwide are affected at some point in their lives. The infection develops when bacteria travel from the urethra or the bladder to the prostate. Treating bacterial prostatitis remains challenging, with patients often requiring long antibiotic treatments at high doses. Even then, more than half of patients suffer a relapse within a year.

For a long time, researchers have suspected that bacteria sneak inside prostate cells to survive and evade the immune system and antibiotics. So far, direct evidence of this survival strategy has been missing.

Until now, studying prostate infections has been difficult because there were no suitable lab models that accurately mimic the real tissue. Hence, without a way to observe infections in the real organ environment, developing alternative therapies beyond antibiotics was nearly impossible. That has now changed. A research team at Julius-Maximilians-Universität of Würzburg (JMU) has developed a “mini prostate” organoid model using adult stem cells. This lab-grown model mimics the prostate epithelium in structure and cell diversity. Using this model, the scientists could follow the infection step by step under realistic, controlled conditions and identify exactly how the bacteria attack, providing clear clues for the development of targeted countermeasures.

Dr. Carmen Aguilar, junior research group leader at the Institute of Molecular Infection Biology (IMIB) at the University of Würzburg, led the study with collaborators from the University Hospital Würzburg (UKW), the Helmholtz Institute for RNA-based Infection Research (HIRI), and University of Münster. The team has published the results in the latest issue of the journal Nature Microbiology.

“We showed that E. coli invasion into prostate cells is not a random process, but rather a highly orchestrated operation that exploits a specific weak point in the cellular architecture of the prostate epithelium,” explains Carmen Aguilar. According to their findings, E. coli is not able to attack indiscriminately, but instead concentrates on a specific cell type: the so-called luminal cells, which line the glandular ducts of the prostate and are the first to come into contact when the bacteria reach the prostate.

This invasion works according to a “lock and key principle.” The bacterial protein FimH acts as a “key” that fits exactly into a “lock” on the surface of the prostate luminal cells. The researchers identified this lock as the prostate-specific receptor PPAP (prostate-specific acid phosphatase). “Only when the bacterial protein binds to this prostate receptor can the bacteria enter the cells, multiply safely inside, and establish the infection,” explains Aguilar.

However, the team did not stop at discovering the infection pathway. They also identified a way to block this interaction using a simple sugar molecule called D-mannose. This sugar, already used to prevent and treat bladder infections, acts as a “dummy lock”. The bacterial “key” binds to these harmless sugar molecules instead of the receptors on prostate cells, effectively blocking bacterial invasion. In the laboratory, the administration of D-mannose has already led to a significant reduction in infection, suggesting a potential new strategy to prevent and treat prostate infections.

The breakthrough organoid model now gives researchers a powerful tool to study prostate infections in unprecedented detail. Using this system, Dr. Aguilar’s team is now investigating how E. coli survives and multiplies within prostate cells after invasion. Moreover, beyond E. coli, the model allows scientists to study infection strategies of other relevant prostate pathogens, such as Klebsiella or Pseudomonas.

“In light of the current antibiotic resistance crisis, our goal is to develop new therapies that can fight E. coli and other bacteria without relying on antibiotics. To achieve this, we first need to fully understand how these infections work,” says Carmen Aguilar. Such approaches could offer an effective alternative to traditional antibiotics and make an important contribution to the fight against antimicrobial resistance.

This work was funded by the Federal Ministry of Research, Technology and Space (BMFTR, FiRe-UPec project) and the German Research Foundation (DFG, GRK 2157 3D Infect).