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Principal Investigator: Richard Brian Meagher
Organization: UNIVERSITY OF GEORGIA
Fiscal Year: 2023
Award: $188,750
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <A fumigatus><A. fumigatus><Address><Aerosols><AmB><AmBisome><Amphocil><Amphotec><Amphotercin B><Amphotericin B><Animal Model><Animal Models and Related Studies><Anti Mycobacterial Agents><Anti-Bacterial Agents><Anti-Infective Agents><Anti-Infective Drugs><Anti-Infectives><Anti-infective Preparation><AntiInfective Drugs><AntiInfectives><Antibacterial Agents><Antibiotic Therapy><Antibiotic Treatment><Antifungal Agents><Antifungal Drug><Antiinfective Agents><Antimycobacterial Agents><Antitubercular Drugs><Area><Aspergillus fumigatus><Assay><Bacterial Infections><Benemycin><Binding><Bioassay><Biologic Assays><Biological Assay><Body Tissues><C albicans><C neoformans><C-Type Lectins><C. albicans><C. neoformans><C.albicans><CD209><CD209 gene><CDSIGN><Candida albicans><Capsid Proteins><Cell Body><Cell Density><Cell Wall><Cells><Cessation of life><Chronic><Coat Proteins><Complex><Cryptococcus neoformans><DC-SIGN><DC-SIGN1><Dangerousness><Data><Death><Development><Disease model><Dose><Drug Delivery><Drug Delivery Systems><Drug Design><Drug Therapy><Drug resistance><Drug toxicity><Drugs><Dysfunction><Family><Functional disorder><Fungizone><Genus Mycobacterium><Glycans><Granuloma><Granulomatous Lesion><Helminths><Human><Immune signaling><Immune system><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunosuppressed Host><In Vitro><Individual><Infection><Infectious Skin Diseases><Isoforms><Kinetics><Laboratories><Laser Scanning Microscopy><Life><Liposomal><Liposomes><Lung><Lung Respiratory System><Lung infections><M avium><M avium Complex><M tb><M tuberculosis><M tuberculosis infection><M ulcerans><M. avium><M. avium Complex><M. avium intracellulare><M. tb><M. tb infection><M. tuberculosis><M. tuberculosis infection><M. ulcerans><M.tb infection><M.tuberculosis infection><MAIC><MTB infection><Medical Device><Medication><Metabolic><Mice><Mice Mammals><Microbial Biofilms><Modeling><Modern Man><Molecular Interaction><Multi-Drug Resistance><Multidrug Resistance><Multiple Drug Resistance><Multiple Drug Resistant><Murine><Mus><Mycobacterial Infection><Mycobacterium><Mycobacterium Infections><Mycobacterium avium><Mycobacterium avium Complex><Mycobacterium avium-intracellulare><Mycobacterium avium-intracellulare Complex><Mycobacterium buruli><Mycobacterium tuberculosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><Mycobacterium ulcerans><Mysteclin-F><Oligo><Oligonucleotides><Oral><Organ><Outcome><Parasitic Worms><Pathogenesis><Pathogenicity><Patients><Peptide/Protein Chemistry><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacotherapy><Physiopathology><Pilot Projects><Polysaccharides><Population><Protein Chemistry><Protein Isoforms><Protozoa><Protozoal><Publications><Publishing><Receptor Protein><Refractory><Research><Resistance to Multi-drug><Resistance to Multidrug><Resistance to Multiple Drug><Resistant to Multiple Drug><Resistant to multi-drug><Resistant to multidrug><Rhodamine><Rifadin><Rifampicin><Rifampin><Rimactane><Scientific Publication><TB drugs><TB infection><Technology><Testing><Therapeutic Fungicides><Thick><Thickness><Tissues><Toxic effect><Toxicities><Toxin><Treatment Protocols><Treatment Regimen><Treatment Schedule><Tuberculosis><Variant><Variation><Viral Coat Proteins><Viral Outer Coat Protein><anti-TB drugs><anti-bacterial><anti-fungal><anti-fungal agents><anti-fungal drug><anti-tuberculosis drugs><antibacterial><antifungals><antimycobacterial><antituberculosis drugs><aspirate><bacteria infection><bacteria pathogen><bacterial disease><bacterial disease treatment><bacterial infectious disease treatment><bacterial pathogen><biofilm><communicable disease control agent><cost><crosslink><cutaneous infection><dectin 1><dectin-2><design><designing><develop drug resistance><developmental><disorder model><disseminated TB><disseminated tuberculosis><drug development><drug efficacy><drug resistance development><drug resistant><drug treatment><drug/agent><effective therapy><effective treatment><experience><experiment><experimental research><experimental study><experiments><extracellular><fungal pathogen><fungi pathogen><fungus><immunosuppressed patient><improved><in vivo><infected skin><infection due to Mycobacterium tuberculosis><innovate><innovation><innovative><intravenous injection><lipid based nanoparticle><lipid nanoparticle><lipomannan><medical implant><member><model of animal><mouse dectin-2><mouse model><mtb><multi-drug resistant><multidrug resistant><murine model><mycobacterial><mycolactone><nanoparticle therapy><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><non-tuberculosis mycobacteria><non-tuberculosis mycobacterial><non-tuberculous mycobacteria><non-tuberculous mycobacterial><nontuberculosis mycobacterial><nontuberculous mycobacteria><nontuberculous mycobacterial><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><oligos><pathogen><pathogenic bacteria><pathogenic fungus><pathophysiology><pilot study><pulmonary><pulmonary infections><receptor><resistance strain><resistance to Drug><resistant strain><resistant to Drug><skin infection><skin lesion><therapeutic nanoparticles><tuberculosis drugs><tuberculosis infection><tuberculous spondyloarthropathy>