Targeted pan-antibacterial liposomes to control pathogenic mycobacteria

点击翻译按钮获取中文摘要

DectiSomes are lipid nanoparticles carrying an anti-infective drug and coated with pathogen receptor that targets them to pathogenic cells. DectiSomes reduce the effective dose for inhibition and killing of pathogens by order(s) of magnitude relative to conventional drugs, potentially overcoming the barriers of multidrug resistant and persister cells. Herein we propose the initial development of pan-antibacterial DectiSomes, testing them against three pathogenic mycobacterial species. One quarter of the world’s population have latent or active TB infections caused by Mycobacterium tuberculosis. There are several million new cases of TB and 1.7 million deaths every year. M. avium and M. ulcerans cause life-threatening pulmonary and dangerous skin infections, respectively and are excellent laboratory models of TB. Pathogenic mycobacteria and fungal pathogens have cell walls and extensive exopolysaccharide matrices rich in oligoglycans and oligolipoglycans. The C-type lectin pathogen receptors Dectin-1 (DEC1), Dectin-2 (DEC2) and DC-SIGN (DCS12) recognize diverse crosslink variants of these oligoglycans and signal the immune system of a pathogen infection. In previously publications we’ve shown that antifungal drug loaded DectiSomes coated with DEC1, DEC2 and DCS12 effectively target and kill diverse fungal pathogens both in vitro and in vivo in mouse disease models. Our working hypothesis for this proposal is that antibacterial drug loaded liposomes targeted to pathogenic bacterial by pathogen receptors will be far more efficacious than untargeted antibacterial drugs. Our strong preliminary data supporting this hypothesis show that rhodamine red fluorescent liposomes coated with Dectin- 1, Dectin-2 and DCS12 bound to M. avium cells and their exopolysaccharide matrix orders of magnitude more strongly than untargeted liposomes or protein coated control liposomes. To further explore this hypothesis, we will pursue the following Specific Aims. 1. Determine the efficiency and kinetics of receptor targeted rifampin RIF-Loaded Liposomes DEC1-RIF-LLs, DEC2-RIF-LLs and DCS12-RIF-LLs binding to M. tuberculosis, M. avium and M. ulcerans grown under various conditions in vitro. 2. Determine the effective dose (ED) of RIF delivered by DEC1-RIF-LLs and DEC2-RIF-LLs for 95% inhibition and/or killing (ED95) of in vitro grown M. tuberculosis, M. avium and M. ulcerans and demonstrate improved drug efficacy. 3. Using a mouse model of TB (i.e., infected with M. tuberculosis), demonstrate that DEC1-RIF-LLs and DEC2-RIF-LLs delivered by oral aspiration and/or intravenous injection dramatically lower the effective dose for 95% reduction in fungal burden (ED95) and improve lung pathophysiology, relative to untargeted RIF-LLs and free RIF. The expected outcome is a precision targeted antibacterial system of drug delivery that reduces the effective dose and number of treatments to control pathogenic mycobacterial infections and hence may reduce drug toxicity to patients. We believe that once developed DectiSome-related technologies will provide the dramatic leap forward needed to overcome the serious current limitations to antibacterial drug development.