Aminoglycosides are one of the cheapest and well-known antibiotics in clinical use for over 70 years, but one of the major limitations in their use is their ototoxicity. We are developing fast and low cost methods to develop aminoglycosides with anti- ribosomal activities and reduced toxicity. In this project, we will identify novel aminoglycoside antibacterials, that show reduced ototoxicity. Complexes between ribosomal components will be exploited as targets for small molecule drug libraries that- inactivate the ribosome, stopping bacterial protein synthesis and causing bacterial death while reducing toxicity. This work addresses an important health issue, antibiotic ototoxicity, and presents creative steps towards a novel solution to this problem. The work proposed here, a multidisciplinary effort encompassing antibacterial screening and ototoxicity studies using zebrafish and guinea pig models, describes the development of novel aminosugar rRNA binders as non-toxic antibacterial therapeutics. The success of the proposed work would be a significant addition to currently available approaches in antibacterial therapy. We propose using a zebrafish assay to identify conjugates that show reduced toxicities, opening possibilities for developing reduced toxicity RNA targeted aminosugar therapeutics.
Public Health Relevance Statement: PROJECT(NARRATIVE The proposed project presents a strategy for developing novel aminoglycoside therapeutics with reduced ototoxicities with evasion of resistance. Antimicrobial resistance occurs when microorganisms (often infectious bacteria, viruses, and certain parasites) are no longer sensitive to drugs that were previously used to treat them; this is of global concern because it hampers our ability to control infectious disease and increases the costs of health care. In order to combat this world-wide problem, innovative strategies for antibiotic drug design must be implemented. The proposed research describes a strategy for improving the therapeutic index of aminoglycosides by designing novel structures that lower their ototoxicity and evade common resistance pathways.
Project Terms: adulthood; Adult Human; 21+ years old; Adult; Biklin; Biclin; Amukin; Amiklin; Amikin; Amikacin; aminoacid; Amino Acids; aminosugar; Amino Sugars; Aminoglycosides; Miscellaneous Antibiotic; Antibiotic Drugs; Antibiotic Agents; Antibiotics; Awareness; Bacteria; bacterial disease; Bacterial Infections; Bacterial Gene Proteins; Bacterial Gene Products; Bacterial Proteins; Biologic Assays; Bioassay; Assay; Biological Assay; Books; Boston; Chemistry; Infectious Disorder; Infectious Diseases; Infectious Disease Pathway; Communicable Diseases; meeting reports; Congresses; Death; Cessation of life; Drug Design; resistant to Drug; resistance to Drug; drug resistant; Drug resistance; drug/agent; Pharmaceutic Preparations; Medication; Drugs; Pharmaceutical Preparations; Environment; U-Gencin; Genoptic S.O.P.; Genoptic; Garamycin; Garamicin; Gentamicins; ontogeny; Tissue Growth; Generalized Growth; Growth; ear hair cell; Corti Cell; Hair Cells; Health; Modern Man; Human; In Vitro; Infection; NAS/IOM; Institute of Medicine; Institute of Medicine (U.S.); Larva; heavy metal lead; heavy metal Pb; Pb element; Lead; Libraries; Marketing; Methods; Murine; Mice Mammals; Mice; Mus; National Academy of Sciences; United States National Academy of Sciences; in vitro vertebrate organ culturing; in vitro Organ Culturing; Organ Culture; Organ Culture Techniques; Parasites; Parents; Peptides; Pigments; Pseudomonas pyocyanea; P.aeruginosa; P. aeruginosa; Pseudomonas aeruginosa; Research; Research Institute; Ribosomes; Ribonucleic Acid; RNA Gene Products; Non-Polyadenylated RNA; RNA; rRNA; Ribosomal RNA; South Carolina; Staph aureus; S.aureus; S. aureus; Staphylococcus aureus; Testing; Time; Translations; United States; Universities; Virus; General Viruses; Work; Zebrafish; Zebra Fish; Zebra Danio; Danio rerio; Brachydanio rerio; Health Care Costs; Healthcare Costs; Health Costs; Antibiotic Resistance; antibiotic resistant; Resistant to antibiotics; Resistance to antibiotics; Auditory Brainstem Responses; Cavia; Guinea Pigs Mammals; Guinea Pigs; Enhancers; promoter; promotor; Green Fluorescent Proteins; bacterial resistance; resistant to Bacterial; resistant to Bacteria; resistance to Bacterial; resistance to Bacteria; Bacterial resistant; Bacteria resistant; Bacteria resistance; method development; improved; Solid; Clinical; Phase; Medical; institutional infection; Hospital acquired infection; Hospital Infections; Nosocomial Infections; Link; Blood Serum; Serum; Sensory Hair; kidney function; Renal function; ototoxicity; Measurement; antibacterial; anti-bacterial; Antibacterial Agents; Anti-Bacterial Agents; Therapeutic; antimicrobial agent; anti-microbial drug; anti-microbial agent; antimicrobial drug; Auditory; Complex; Protocol; Protocols documentation; microorganism; lateral line; Surgeon; membrane structure; Membrane; mutant; protein synthesis; Ribosomal Protein Synthesis; Ribosomal Protein Biosynthesis; Ribosomal Peptide Biosynthesis; Protein Biosynthesis; success; neuromast; cell damage; Cellular injury; cell injury; model organism; Animal Models and Related Studies; Animal Model; transgenic; Transgenic Organisms; Toxicities; Toxic effect; Structure; Therapeutic Index; novel; Modeling; High Throughput Assay; high throughput screening; Molecular Interaction; Binding; small molecule; biodefense; Address; resistant to antimicrobial; resistant to anti-microbial; resistance to anti-microbial; anti-microbial resistant; anti-microbial resistance; Resistance to antimicrobial; Antimicrobial resistant; Antimicrobial Resistance; CBA/J Mouse; in vivo; developmental; Development; pathway; Pathway interactions; cost; designing; design; pathogen; Coupled; innovation; innovative; innovate; Resistance; resistant; antimicrobial; anti-microbial; multidisciplinary; combat; screening
