Engineering capsosomes for improved treatment of intracellular bacterial infections
Medical Physics, Biomedical Technology
Final Report Abstract
The current Covid-19 situation makes clear that pandemics effect human life on multiple levels. Before the discovery of antibiotics outbreaks caused by bacteria were frequently reported. One of the worst pandemic in human history was in the 13 th century due to Yersinia pestis (black plaque) which cost millions of lives. Antibiotics are powerful drugs to prevent or treat bacterial infections and key element for the success of modern medicine (e.g. surgery, the survival of pre-term infants and transplantation). In the last decades the massive over- and misuse of antibiotics led to an increase in antimicrobial resistant (AMR) bacteria resulting in a shortage of effective drugs. Moreover, antibiotic treatment is limited by deficient drug concentration at the site of infection and cytotoxicity leading to severe side effects. According to the WHO a “post-antibiotic area is near in which minor injuries and common infectious diseases may be mortal again”. Unquestionable, there is an urgent need for novel therapeutic strategies to overcome the global AMR problem. In this DFG Fellowship a nanotechnology based approach was investigated in order to generate an antibiotic drug delivery platform. Capsosomes are nanocarriers composed of alternating polymer and liposome layers with the advantage of a triggered drug release, a high loading capacity and the delivery of multiple drugs. In course of this multidisciplinary project capsosomes with different liposome composition were successfully synthesised. Thereby, up to 4 layers of polymer and liposomes were achieved enable a tremendous loading capacity for antimicrobial compounds. The lipid formulation was optimised in terms of stability and drug loading capability. The smart liposome composition also enables a triggered release of antibiotic only in presence of toxin-producing bacteria. A key advantage of capsosomes is the co-delivery of drugs within liposomes and the core. The combination of antibiotic is beneficial in terms of broader antimicrobial coverage, higher antibiotic efficacy and suppressing the emergence of resistance. In this project capsosomes were successfully loaded with two different antibacterial compounds. Protamine an antimicrobial peptide was successfully loaded in the mesopourus silica core whereas, vancomycin, a glycopeptide antibiotic was incorporated into lipsosomes. Interestingly, due to electrostatic interaction Gram-positive as well as Gram-negative bacteria localising around the generated capsosomes. This observation could be important for future application by which the shorter antibiotic travel distance may results in reduced antibiotic therapy. Of interest, antibacterial tests revealed that the capsosomes loaded with vancomycin and protamine show antibacterial activity against S. aureus Je2 (MRSA strain) a relevant multidrug resistant human pathogen. Overall, this DFG project highlights clearly that multidisciplinary work is the key to find novel strategies to tackle bacterial infectious diseases. The data generated in this project display that capsosomes are a promising bioengineered antibiotic delivery system. This nanocarriers are incredible tuneable in terms of deliverable payload, triggered drug release and co-delivery and can be tailored for specific bacterial diseases. Therefore, they offer an attractive alternative to systemic monotherapy and a novel approach to fight bacterial infections.
Publications
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Colistin requires de novo lipopolysaccharide biosynthesis for activity. BioRxiv
Akshay Sabnis, Anna Klöckner, Michele Becce, Lindsay E. Evans, Molly M. Stevens and Andrew M. Edwards
