Novel Approaches to Antibacterial Delivery Systems and Light-Activated Antibiotics

Abstract

The rapid emergence of bacterial infections, including resistant bacteria or biofilms, is occurring worldwide. There is an urgent need for the development of new strategies to fight against them. Implementation of several approaches such as discovering new antibiotics or targets, avoidance of drug accumulation in the environment, or improvement in the delivery of antimicrobials is promising to overcome this crisis. In this thesis, three projects are presented consisting of 1) semi-synthetic modification of antibiotics to combat against bacterial resistance and biofilm formation, 2) design and synthesis of light-regulated antibiotics for the control of their biological activity, and 3) development of new delivery systems based on biohybrid microswimmers. In the first project, the incorporation of sulfur-containing moieties into the structure of two antibiotics – vancomycin and cephalosporin demonstrated the improvement of their antibacterial activity against resistant strains and biofilm formation. In the second project, the two abovementioned antibiotics were enhanced in their performance by rendering them photoresponsive. The antimicrobial activity of the antibiotics could be “caged” and spatiotemporally controlled by light, displaying excellent inhibition of bacterial growth after uncaging. In the third project, the development of biohybrids based on Chalamydomonas reinhardtii is reported. The antibiotics were attached to the microalgae surface via a photo-cleavable linker. The guided and safe delivery of the antibiotics without the loss of the cargo and controlled drug release was achieved to combat bacterial infections with high precision in space and time. Overall, this work presents several different approaches to fight against bacterial infections.