Unveiling the structure, function and dynamics of StmPr1 in Stenotrophomonas maltophilia virulence

Introduction

The globally rising number of deaths related to multi-resistant Gram-negative bacteria has emerged to be one of the most challenging clinical and public health problems during the last years^1,2. While immense progress in pharmaceutical and drug discovery research has been achieved, it remains a challenge to treat several distinct infectious diseases. Particularly nosocomial infections caused by opportunistic Gram-negative pathogens are increasingly difficult to treat, caused by rising intrinsic and acquired antibiotic resistance³. A Gram-negative multi-resistant opportunistic pathogen of increasing relevance is Stenotrophomonas maltophilia. S. maltophilia is a non-fermenting Gram-negative bacillus that can be isolated globally. It is found in different environmental sources, such as water, soil, sediment, plants, and animals^{4, 5, 6, 7–8}. Despite not being inherently virulent, it causes serious infections in immunocompromised patients, including pneumonia, catheter-associated bacteremia/septicemia, osteochondritis, mastoiditis, meningitis, and endocarditis. It is associated with crude mortality rates ranging from approx. 15% to 70% in bacteremia patients^{9, 10, 11–12}. Due to its role in nosocomial infections, S. maltophilia has increasingly become the focus of biomedical research over the last two decades. Reported S. maltophilia cases are rising considerably, becoming the most common Gram-negative carbapenem-resistant pathogen found in bacteremia particularly in hospitals^13,14. Besides carbapenem, it is intrinsically resistant to multiple antibiotics, including multiple broad-spectrum antibiotics¹². The bacterium is frequently found in patients with cystic fibrosis, with the frequency ranging from 10 to 30%¹⁵. During the COVID-19 pandemic, S. maltophilia was identified to be the main pathogen involved in respiratory co-infections and bacteremia in critically ill COVID-19 patients. S. maltophilia found in sputum samples of such patients showed the highest rates of multidrug resistance among bacteria infecting COVID-19 patients^{16, 17–18}. This role in polymicrobial bacterial communities is of increasing relevance given its ability to influence neighboring microorganisms’ metabolism by antagonistic suppression or by symbiotic coexistence. S. maltophilia colonizes cystic fibrosis patients alongside Pseudomonas aeruginosa, Staphylococcus aureus, or Burkholderia cenocepacia^19,20. Besides its role in polymicrobial bacterial communities, S. maltophilia shows a broad spectrum of virulence factors consisting of surface cell-associated structures and a wide spectrum of extracellular enzymes²¹. Our investigation focused on obtaining insights into the structure-function-relationship of one of the main...