Bacterial infections represent a major concern for today’s healthcare system, especially in nosocomial settings where frail and immunocompromised patients are threatened by increasingly drug-resistant pathogens. Since antimicrobial resistance leads to high morbidity and mortality, there is a pressing need to develop alternative antimicrobial therapies to which bacteria can neither adapt nor acquire resistance. Bacteria-targeted antimicrobial photodynamic therapy (aPDT) can potentially meet this challenge. Targeted aPDT relies on the combination of a targeting agent that is chemically coupled to a photo-activatable drug that is referred to as photosensitizer. Upon activation by light, the bacteria-targeted photosensitizer will generate reactive oxygen species that simultaneously destroy multiple essential components of the targeted bacterial cells. The present PhD research was aimed at identifying effective targeting molecules for aPDT of infections caused by methicillin-resistant Staphylococcus aureus (MRSA). These targeting molecules included S. aureus-specific monoclonal antibodies, or molecules with a much broader target spectrum, such as antibiotics or the bacteria-binding domain from a bacteriophage. The different molecules were conjugated to a near-infrared photosensitizer, which is already clinically applied in anti-cancer PDT. This resulted in a portfolio of novel conjugates for targeted aPDT, which were shown to be highly effective in killing MRSA. Notably, these conjugates were even effective when the bacteria were hiding within human cells, or in hard-to-eradicate multicellular communities known as biofilms. Altogether, the results show that targeted aPDT holds great promise for clinical application in the treatment of bacterial infections, even if the bacteria are highly resistant to antibiotics.
|Qualification||Doctor of Philosophy|
|Place of Publication||[Groningen]|
|Publication status||Published - 2021|