S. pneumoniae is an important pathogenic streptococcus which causes invasive diseases such as sepsis, meningitis, and pneumonia. In a recent annual report on global risks, the World Economic Forum concluded that “arguably the greatest risk to human health comes in the form of antibiotic-resistant bacteria”. This urgently necessitates further search for new antibiotics.
The colonization and virulence of pathogenic streptococci displays a clear dependence on trace metal ion homeostasis systems, thus there could be possibilities to use these systems as targets for anti-infective therapies. Zinc is a pivotal metal ion in the interaction of pathogenic streptococci with the host. Zinc uptake is of crucial importance for the virulence of streptococci, whereas elevated zinc levels induced in the host during infection are detrimental for these pathogens. The expression or activity of a number of putative surface proteins and virulence factors depend on zinc. Moreover, several metal sensor proteins that mediate the transcriptional response to zinc in streptococci have recently been characterized. A number of components of zinc- and other metal ion-acquisition systems may provide opportunities for the development of novel therapies (Shafeeq 2013).
Lanthipeptides are post-translationally modified antimicrobial peptides produced by bacteria from diverse environments. A major hurdle in the application of therapeutic peptides is their rapid degradation by peptidases. Lanthionines, which can be introduced by lantibiotic modification enzymes, effectively protect therapeutic peptides against breakdown, thereby strongly increasing bioavailability, enabling oral and pulmonary delivery and potentially significantly optimizing the receptor interaction of selected variants. To efficiently select optimal variants, a library of DNA-coupled lanthionine-stabilized peptides is highly desirable. Such a very elegant system has been developed in the lab of Prof. Moll (Bosma et al., 2011).
Fig.1. Lactococcus cell-surface lanthipeptide display system. The lanthipeptides are coupled to the cell wall and thereby a link with the plasmid encoding DNA is in place. Per individual cell in the order of a few thousand identical lanthipeptides are displayed.
Obtention of successful Zn-transporter-inhibitor lanthipeptides, which could efficiently kill the pathogenic bacteria (S. pneumoniae).
Bacterial display and FACS screen.
- Bosma, T., Kuipers, A., Bulten, E., de Vries, L., Rink, R., Moll, G.N. 2011. Bacterial display and screening of posttranslationally thioether-stabilized peptides. Applied and environmental microbiology, 77(19), 6794-6801.
- Shafeeq, S., Kuipers, O.P., Kloosterman, T.G. 2013. The role of zinc in the interplay between pathogenic streptococci and their hosts. Molecular microbiology, 88(6), 1047-1057.