Abstract by Emilie Marie Ochsner
The escalating threat of antimicrobial resistance in bacteria has become a growing concern for global health, and currently it accounts for 9 % of all global deaths. Antimicrobial resistance occurs when bacteria naturally resist or acquire the ability to survive antimicrobial treatments, often due to inappropriate and overuse of antibiotics. Two bacterial species responsible for numerous severe infections are Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa), both listed on World Health Organization’s list of critical pathogens for which “new antibiotics are urgently needed”. As bacteria develop resistance faster than new antibiotics are developed, there is an urgent need for new treatment strategies.
Antimicrobial peptides, particular host defence peptides (HDPs), are promising alternatives to conventional antibiotics, due to their broad-spectrum antimicrobial and antibiofilm activities. Moreover, they display immunomodulatory properties that help defend against bacterial infections. A key advantage of HDPs is that they are less prone to trigger resistance development in bacteria, due to their multiple modes of action and diverse molecular targets. Using HDPs as alternative treatment strategies may enhance treatment efficacy and improve patient survival by both killing bacteria and modulating the immune response. Unfortunately, the use of HDPs is not straight forward, as their antimicrobial activity is compromised under physical conditions and pathologies.
In this thesis, the role of bacterial membrane vesicles (MVs) in the attenuated activity of the HDPs was explored. Bacteria actively secrete MVs during growth and infection, and these MVs serve various functions, including contribution to antimicrobial protection by acting as a decoy that binds antimicrobial agents, thereby protecting the bacteria.
To achieve this, we investigated MVs secreted from both Gram-positive and Gram-negative bacteria and their interplay with three different human-derived HDPs, to assess whether MV-HDP interactions are general or HDP-specific.
Manuscript I showed that spontaneous secreted MVs from S. aureus and P. aeruginosa inhibited the antimicrobial activity of all three HDPs upon binding. Moreover, HDP-bound MVs showed a reduced immunogenicity. These results indicate that bacteria secrete MVs as decoys to sequester HDPs and diminish their antibacterial activity, while also reducing MV-induced immune activation.
P. aeruginosa is a potent immune evader that frequently forms biofilm during infections, enhancing its resistance to antimicrobial agents and promoting persistence within the host.
Manuscript II showed that sub-lethal concentrations of KYE28 increased MV secretion and protein concentration in planktonically grown P. aeruginosa. However, in biofilm-associated P. aeruginosa higher concentrations of KYE28 were needed to modulate MVs. MVs secreted both in the absence and presence of KYE28 attenuated the peptide’s antimicrobial activity. Additionally, KYE28 exhibited dose-dependent antibiofilm activity, although the biofilm matrix provided some protection to the bacteria.
Collectively, these findings demonstrate that bacteria secrete MVs as an immune evasion strategy to evade antimicrobial agents. Both spontaneously secreted and HDP-induced MVs bind to HDPs, attenuating their antibacterial activity while supressing MV-mediated immune activation. The comparable findings across MVs from both Gram-positive and Gram-negative bacteria indicate a general vesicle-mediated mechanism of immune evasion. Taken together, this highlights the dynamic interplay between HDPs and MVs as part of bacterial defence mechanisms and emphasize the complex interactions between HDPs and bacteria. These insights underscoring the importance of continued research to optimize HDP-based therapies capable of effectively counteracting bacterial resistance mechanisms.