Friday, April 06, 2007
Targeted drug-carrying bacteriophages as anti bacterial nanomedicines.
Antimicrob Agents Chemother. 2007 Apr 2
Department of Molecular Microbiology and Biotechnology, The George S. wise faculty of Life Sciences, and Department of Organic Chemistry School of Chemistry, Tel-Aviv University, Ramat Aviv 69978, Israel.
While the resistance of bacteria to traditional antibiotics is a major public health concern, the use of extremely potent antibacterial agents is limited by their lack of selectivity. As in cancer therapy, anti bacterial targeted therapy could provide an opportunity to re-introduce toxic substances to the anti-bacterial arsenal. A desirable targeted anti-bacterial agent should combine binding specificity, a large drug payload per binding event and a programmed drug release mechanism. Recently we presented a novel application of filamentous bacteriophages as targeted drug carriers that could partially inhibit the growth of Staphylococcus aureus bacteria.
This partial success was due to limitations of drug-loading capacity that resulted from the hydrophobicity of the drug. Here we present a novel drug conjugation chemistry which is based on connecting hydrophobic drugs to the phage via aminoglycoside antibiotics that serve as solubility-enhancing branched linkers. This new formulation allowed a significantly larger drug-carrying capacity of the phages resulting in a drastic improvement in their performance as targeted drug carrying nanoparticles. As an example for a potential systemic use for potent agents that are limited for topical use, we present antibody-targeted phage nanoparticles that carry a large payload of the hemolytic antibiotic chloramphenicol connected through the aminoglycoside neomycin.
We demonstrate complete growth inhibition towards the pathogens Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli with an improvement in potency by a factor of approximately 20,000 as compared to the free drug.
Antimicrobial Agents and Chemotherapy