Aminoglycosides with reduced ototoxicity

具有降低耳毒性的氨基糖苷类

• 批准号: 10377538
• 负责人: DEV PRIYA ARYA
• 金额: $ 99.97万
• 依托单位: NUBAD, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10377538
• 关键词: ADME Study; Abdominal Infection; Address; Amikacin; Aminoglycosides; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Auditory; Auditory Brainstem Responses; Awareness; Bacillus; Bacteria; Bacterial Infections; Bacterial Pneumonia; Bacterial Proteins; Biodistribution; Biological Assay; Biological Availability; Biology; Books; COVID-19; COVID-19 morbidity; COVID-19 mortality; Cavia; Cell Wall; Cessation of life; Chemistry; Clinical; Colistin; Communicable Diseases; Complex; Congresses; Coronavirus; Coupled; Creativeness; Development; Disease; Dose; Drug Design; Drug Interactions; Drug Kinetics; Drug Targeting; Drug resistance; Enterobacteriaceae; Excretory function; Family; Feedback; Fiber; Growth; Hair Cells; Health; Health Care Costs; Hospitals; Human; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Institute of Medicine (U.S.); Intervention; Intra-abdominal; Klebsiella pneumoniae; Knowledge; L Forms; Lead; Legal patent; Length of Stay; Lethal Dose 50; Libraries; Liver Microsomes; Lung diseases; Lung infections; Measurement; Medical; Metabolism; Methods; Microbial Biofilms; Minimum Inhibitory Concentration measurement; Modeling; Modernization; Modification; Multi-Drug Resistance; Mus; Nosocomial Infections; Nucleic Acids; Organ Culture Techniques; Parasites; Pathogenicity; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Phase; Pneumonia; Population; Proliferating; Protein Biosynthesis; Protocols documentation; Pseudomonas aeruginosa; RNA; RNA Binding; Rapid screening; Rattus; Renal function; Reporting; Research; Resistance; Resistance profile; Ribosomes; Risk; Risk-Benefit Assessment; Role; Sensory Hair; Sepsis; Serum; Severe Acute Respiratory Syndrome; Severities; Societies; Solid; South Carolina; Structure; Superbug; Surgeon; Testing; Therapeutic; Therapeutic Index; Thigh structure; Time; Toxic effect; United States; United States National Academy of Sciences; Universities; Urinary tract infection; Viral; Virus; Work; World Health Organization; Zebrafish; absorption; aminoglycoside-induced ototoxicity; antibiotic resistant infections; antimicrobial drug; antimicrobial resistant infection; bacterial resistance; candidate identification; carbapenem resistance; carbapenem-resistant Enterobacteriaceae; combat; cost; design; economic impact; efficacy study; extensive drug resistance; follow-up; guinea pig model; improved; in vivo; in vivo Model; inhibitor; innovation; method development; microorganism; mortality; multidisciplinary; novel; novel antibiotic class; novel therapeutic intervention; novel therapeutics; ototoxicity; pandemic influenza; pathogen; pathogenic bacteria; phase 1 study; pre-Investigational New Drug meeting; pre-clinical; preclinical toxicity; priority pathogen; rapid technique; rapid test; screening; small molecule; standard of care; success; synergism; tigecycline

PROJECT SUMMARY 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. Cases of multidrug-resistant (MDR, resistance to 2-3 classes), extensive drug resistance (XDR, resistance to most classes except colistin or tigecycline) and even pan drug resistance (PDR, resistance to all classes) nosocomial bacterial infections have skyrocketed in recent years, and the emergence of pan drug- resistant isolates are making these infections increasingly difficult to treat. Hospital-acquired infections like these account for up to 4% of all hospital stays in the United States and are incredibly diverse in causative pathogen, antibiotic resistance profile, and severity. A significant cause of nosocomial infection is the Enterobacteriaceae family, which includes Gram-negative bacilli that can be commensal or pathogenic. Enterobacteriaceae have a widespread clinical and economic impact due to the diversity of infections they cause; this family causes many infections such as pneumonia, bloodstream infections (BSIs), urinary tract infections (UTIs), and intra-abdominal infections (IAIs). The World Health Organization (WHO) lists carbapenem-resistant Enterobacteriaceae (CRE) as having a critical need for novel antibiotics on their Priority Pathogens list. Because the mortality of these multi drug-resistant infections is between 30 and 50% and there is such difficulty in finding viable treatments, the need for novel therapeutics for these pathogens must be addressed. 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. Influenza and coronavirus (SARS and COVID-19) create an even more urgent need for targeting resistant bacteria related to lung infections, such as carbapenem-resistant Enterobacteriaceae (CRE), a common example of CRE being Klebsiella Pneumoniae (KP). A recent article by J. Gerberding, former CDC director states, “The patients at greatest risk from superbugs like CRE, CR-A. buamanii and CR-P. aeruginosa and other bacterial pathogens that can cause lung diseases, are the ones who are already more vulnerable to illness from viral lung infections like influenza, severe acute respiratory syndrome (SARS), and COVID-19. The 2009 H1N1 influenza pandemic, for example, claimed nearly 300,000 lives around the world. Many of those deaths — between 29% and 55% — were actually caused by secondary bacterial pneumonia, according to the CDC.” A recent study (Zhou, Lancet 2020, 395, 1054-1062) from Wuhan reports that almost 50% of COVID-19 related deaths showed evidence of secondary bacterial infections (pneumonia, sepsis, bloodstream infections). Clearly, more work needs to be done to better understand the role of secondary bacterial infections in COVID-19 related morbidities, and develop non-toxic interventions in parallel. One of the challenges of research in infectious diseases is to find ways to use the increasing knowledge of the mechanisms underlying disease biology, transformation and progression to develop novel therapeutic strategies for MDR, XDR, and PDR bacterial infections. Targeting heavily conserved RNA structures, present in the 4 billion years old bacterial ribosome, and involved in proliferation and survival of bacteria, is a promising approach. RNA, the essential nucleic acid component of the ribosome, is a validated target for drug design, both as therapeutic and as a target. The work proposed here, a multidisciplinary effort using rapid methods of synthesis, bacterial inhibition and zebrafish screening assays in Phase I studies, will be further developed in Phase II using in vivo efficacy and ototoxicity studies using guinea pig models. The success of the proposed work would be a significant addition to currently available approaches in antibacterial therapy. We propose using novel aminoglycoside modifications, patented NUBAD assays, and preliminary results from a zebrafish screening assay and mouse organ culture to identify conjugates that show reduced ototoxicities, opening possibilities for developing aminoglycosides that can target resistant pathogens with much improved therapeutic indices.

项目总结