Phase II year
2015
(last award dollars: 2024)
Phase II Amount
$2,332,414
One of the challenges of research in infectious diseases is to find ways to use the increasing knowledge of the mechanisms underlying disease transformation and progression to develop novel therapeutic strategies for diseases such as increasing menace of bacterial infections. Targeting specific RNA, such as rRNA which are involved in proliferation and survival of bacteria is a promising approach. The world is rapidly heading towards a pre-1940's scenario when it comes to fighting infectious disease. Antimicrobial resistance is a growing problem on a global scale, greatly hampering our abilities to quell worldwide epidemics such as tuberculosis and malaria, as well as the simple staphylococcus infection. Unless innovative strategies are developed to produce robust and effective new classes of antibiotics, health care costs will continue to climb and we will completely lose our ability to combat even the most common infection. Nucleic acids are avenues for drug design, both as therapeutics and as targets. Here we propose to establish new methods for identifying antibiotic ribosome targets and lead compounds. We are developing fast and low cost methods to screen sequence-specific small molecules for novel anti-ribosomal activities. We will construct sequence-specific ribosomal targeting oligomers as antibacterials. 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. NUBADs unique experimental approaches and technologies will allow us to target ribosomal regions not previously explored for susceptibility against anti-bacterial agents. This work addresses an important world health issue, antimicrobial resistance, and presents creative steps towards a novel solution to this problem. The work proposed here, a multidisciplinary effort encompassing solid-phase organic synthesis, RNA targeted screening and antibacterial studies, describes the development of sequence-specific cell permeable binders of rRNA as antibacterial therapeutics. The success of the proposed work would be a significant addition to currently available ribosome-specific approaches in antibacterial therapy. We propose using a small rRNA target sequences to design conjugates that can be employed to inhibit bacterial growth, opening possibilities for developing sequence-specific RNA targeted therapeutics.
Public Health Relevance Statement: Public Health Relevance: 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 the design, synthesis, and characterization of novel oligomeric conjugates and their validation as new antibacterials. A targeted library of molecules that can specifically target certain regions of bacterial ribosome and impair their cellular processes, will be developed for the study.
Project Terms: Address; Amino Sugars; Aminoglycosides; Animals; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; antimicrobial; antimicrobial drug; Antimicrobial Resistance; Awareness; Bacteria; Bacterial Infections; Bacterial Proteins; bacterial resistance; Base Pairing; Binding (Molecular Function); Biological Assay; Books; Boston; Bypass; Cell Line; Cell physiology; Cells; Cessation of life; combat; Communicable Diseases; comparative; Complement; Complex; Congresses; cost; design; Development; Disease; Drug Design; Drug resistance; Drug Targeting; Enzymes; Epidemic; Escherichia coli; fighting; Generations; Growth; Head; Health; Health Care Costs; High Pressure Liquid Chromatography; Human; Hybrids; In Vitro; Infection; innovation; Institute of Medicine (U.S.); Knowledge; Lead; Libraries; Link; Locales; Malaria; Marketing; Methods; microorganism; multidisciplinary; National Academy of Sciences (U.S.); Neomycin; Nosocomial Infections; novel; novel therapeutics; Nucleic Acids; Organic Synthesis; Parasites; Peptide Antibiotics; Peptide Nucleic Acids; Pharmaceutical Preparations; Phase; Predisposition; Preparation; Protein Biosynthesis; Reporting; Research; Resistance; Ribosomal RNA; Ribosomes; RNA Binding; RNA Interference; scale up; screening; Site; small molecule; Solid; Solutions; Specificity; Staphylococcal Infections; Structure; success; Surgeon; Tail; Technology; Testing; Therapeutic; therapeutic target; Thiourea; Time; Toxic effect; Translations; Tuberculosis; United States; Universities; uptake; Validation; Virus; web site; Work; World Health
