Host-parasite interplay in pneumococcal infection

Pathogenic bacteria are increasingly resistant to antibiotics. This may lead to a post-antibiotic scenario in which some studies predict, in the mid-term, a higher mortality for this cause than, for instance, cancer diseases. This has fostered our research to focus on the search of novel antimicrobials that circumvent antimicrobial resistance issues.

Among the few alternatives that are glimpsed to treat this problem are endolysins encoded by phages, modular enzymes that hydrolyze specific bonds of bacterial peptidoglycan. New phage endolysins are being tested or by construction of chimeras fusing different functional domains. These enzymes are effective in both planktonic cultures and in biofilms. Specifically, during 2017, the molecular basis of the recognition of the cell wall by endolysin Cpl-7 (encoded by a pneumococcal phage) was studied. In addition, a new chimeric enzyme (Csl2) has been constructed which has shown its bactericidal activity in infections caused by Streptococcus suis, an emerging zoonotic agent. Validation of in vitro results is done in mouse or zebrafish models.

Most chronic infections are caused by bacteria that grow into biofilms. The antibiotic tolerance of these communities is well known. Frequently, the human nasopharynx is colonized by encapsulated pneumococci associated with non-encapsulated pneumococci and non-typeable H. influenzae (NTHi) strains. During 2017 the requirements for the formation of mixed in vitro biofilms between S. pneumoniae and NTHi strains were studied. This model has been used to demonstrate the antibiofilm activity of two antioxidants frequently used in clinical practice: N-acetyl-L-cysteine and cysteamine. Moreover, a novel procedure allowing the specific recognition of S. pneumoniae in mixed cultures has been developed. This method involves the use of the HPA lectin from Helix pomatia.

Pneumococcal surface proteins play an essential role in bacterial viability and virulence, and yet, they have not been considered so far as targets for the development of new antibiotics. We have found a panoply of molecules, from low molecular weight compounds to peptides and proteins, that interfere with the role of these proteins. Moreover, we are employing the concept of chemical multivalency to design and assay nanoparticles containing several copies of the cited active compounds, leading to an exponential increase in antimicrobial activity.

Key words: Streptococcus pneumoniae, virulence, immunity, complement system, carrier state, choline-binding proteins, biofilms, enzybiotics, bacteriophages, structure-function, nanobiotechnology