The role of membrane vesicles in bacterial resistance to antimicrobials and their potential for targeted therapeutic interventions
Name of applicant
Mariena van der Plas
Institution
University of Copenhagen
Amount
DKK 4,724,060
Year
2020
Type of grant
Semper Ardens: Accelerate
What?
Bacterial and host membrane vesicles (MVs) play important roles during infection. Whereas host MVs are released in response to bacteria and may bind and neutralise bacterial toxins, bacterial MVs may counteract detrimental host responses, bind and disable various antibiotics, and may play a role in antibiotic resistance. Antimicrobial host defence peptides (HDPs) are regarded as very promising alternatives to antibiotics. However, it is unknown whether MVs may bind and incapacitate HDPs as well. Therefore, in this project we will focus on understanding the interplay between HDPs and MVs during infection. Additionally, we will study specificity of host MVs, as well as bacterial MVs from different strains, to explore their potential for targeted delivery of antimicrobials.
Why?
Antibiotic resistance development in bacteria has become an increasing issue in human medicine, animal husbandry and agriculture. As more antibiotics have become ineffective, focus has shifted towards alternative antimicrobial therapies such as HDPs, which may not only kill a broad spectrum of microbes, including multi-resistant strains, but also modulate host inflammatory responses. However, the antimicrobial activity of many HDPs is compromised under physiological conditions. Moreover, pathogenic bacteria may mimic the formation of HDPs to evade host responses. Therefore, the use of HDPs as antimicrobials is not as straightforward as once thought, and understanding extracellular resistance mechanisms of bacteria towards the antimicrobial activity of HDPs is essential.
How?
In order to address the roles of host and bacterial MVs in relation to the function of HDPs, we will investigate the effect of various HDPs on bacterial and host MV release, composition and function. We will also investigate how binding of HDPs to these vesicles affect the biological activity of the peptides. For this purpose, we will use a broad range of methods within physical chemistry, molecular biology, microbiology, cell biology, immunology, microscopy, and proteomics. Furthermore, we will investigate how HDP-MV binding affect bacterial recognition and antibacterial responses by host cells. Finally, we will investigate the existence of species selectivity of MVs.