Alternatives to antibiotics

Abstract

Antibiotic resistance is a growing problem, leading to ineffective antibiotic treatments, causing bacterial infections to be lethal again. Therefore, new alternatives are needed to fight bacterial infections. Targeting bacterial quorum sensing, might be a promising approach. Quorum sensing (QS) is a bacterial communication system via which bacteria regulate their gene expression based on cell density. In other words, when there are a lot of bacteria, different genes are activated that are beneficial for collaboration. These genes include genes involved in virulence factor production (which cause tissue damage) and biofilm formation (which makes the bacteria less susceptible for antibiotics). Therefore, inhibition of QS might have beneficial effects, including less tissue damage and higher susceptibility to antibiotics. QS inhibitors have also shown positive outcomes in animal models. However, the role of QS during human infections is still underexplored. In this thesis, we focused on the potential of QS inhibition as alternative treatment against bacterial infection. We searched for novel QS inhibitors using a library of more than 10,000 fungal filtrates. This showed that natural compounds produced by fungi still hold great promise to find novel QS inhibitors since various active compounds were identified. Paecilomycone showed the greatest potential by limiting production of virulence factors and biofilm formation in P. aeruginosa, a bacteria that is notorious for causing infections in immunocompromised patients, including individuals with CF. In addition, we set up a new platform to study the role of QS during infection using co-cultures of P. aeruginosa bacteria with airway organoids. This research showed that organoids can indeed be used to study the interplay between epithelium and bacteria. The epithelium showed a strong immune response after infection with P. aeruginosa, while P. aeruginosa bacteria upregulated genes involved in infection. However, genes involved with QS were inhibited. This suggests that the role of QS during human infection might be limited. Therefore, we need to focus on learning more about the role of QS during human infection before developing QS into the clinic.