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Principal Investigator: DEV PRIYA ARYA
Organization: NUBAD, LLC
Fiscal Year: 2024
Award: $999,707
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <ADME Study><Abdominal Infection><Absorption, Distribution, Metabolism, and Excretion Study><Active Follow-up><Address><Amikacin><Amikin><Amiklin><Aminoglycosides><Amukin><Anti-Bacterial Agents><Antibiotic Agents><Antibiotic Drugs><Antibiotic Resistance><Antibiotics><Antimicrobial Resistance><Assay><Auditory><Auditory Brainstem Responses><Awareness><Bacillus><Bacteria><Bacteria resistance><Bacteria resistant><Bacterial Gene Products><Bacterial Gene Proteins><Bacterial Infections><Bacterial Pneumonia><Bacterial Proteins><Bacterial resistant><Biclin><Biklin><Bioassay><Bioavailability><Biodistribution><Biological Assay><Biological Availability><Biology><Blood Serum><Books><Brachydanio rerio><COVID associated morbidity><COVID induced morbidity><COVID morbidity><COVID related morbidity><COVID-19><COVID-19 associated death><COVID-19 associated fatality><COVID-19 associated morbidity><COVID-19 associated mortality><COVID-19 death><COVID-19 fatality><COVID-19 induced death><COVID-19 induced fatality><COVID-19 induced morbidity><COVID-19 induced mortality><COVID-19 morbidity><COVID-19 mortality><COVID-19 related death><COVID-19 related fatality><COVID-19 related morbidity><COVID-19 related mortality><COVID19 associated death><COVID19 associated fatality><COVID19 associated mortality><COVID19 death><COVID19 fatality><COVID19 induced death><COVID19 induced fatality><COVID19 induced mortality><COVID19 mortality><COVID19 related death><COVID19 related fatality><COVID19 related mortality><CV-19><Cavia><Cell Wall><Cessation of life><Chemistry><Clinical><Coliform Bacilli><Colimycin><Colisticin><Colistin><Common Rat Strains><Communicable Diseases><Complex><Congresses><Coronaviridae><Coronavirus><Coronavirus Infectious Disease 2019><Corti Cell><Coupled><Creativeness><Danio rerio><Death><Development><Disease><Disorder><Dose><Drug Design><Drug Interactions><Drug Kinetics><Drug Targeting><Drug resistance><Drugs><Enteric Bacteria><Enterobacteria><Enterobacteriaceae><Excretory function><Family><Feedback><Fiber><GAR-936><Generalized Growth><Grippe><Growth><Guinea Pigs><Guinea Pigs Mammals><H1N1><H1N1 Virus><Hair Cells><Health><Health Care Costs><Health Costs><Healthcare Costs><Hospital Infections><Hospital acquired infection><Hospitals><Human><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Influenza><Influenza A Virus, H1N1 Subtype><Institute of Medicine><Institute of Medicine (U.S.)><Intermediary Metabolism><Intervention><Intervention Strategies><Intra-abdominal><K pneumoniae><K. pneumoniae><Klebsiella pneumoniae><Knowledge><L Forms><LD-50><LD50><Lead><Legal patent><Length of Stay><Lethal Dose 50><Libraries><Liver Microsomes><Lung Diseases><Lung infections><Measurement><Medical><Medication><Metabolic Processes><Metabolism><Methods><Mice><Mice Mammals><Microbial Biofilms><Minimum Inhibitory Concentration measurement><Minimum Inhibitory Concentrations><Miscellaneous Antibiotic><Modeling><Modern Man><Modernization><Modification><Multi-Drug Resistance><Multidrug Resistance><Multiple Drug Resistance><Multiple Drug Resistant><Murine><Mus><NAS/IOM><National Academy of Sciences><Non-Polyadenylated RNA><Nosocomial Infections><Nucleic Acids><Number of Days in Hospital><Organ Culture><Organ Culture Techniques><P aeruginosa><P. aeruginosa><Parasites><Patents><Pathogenicity><Pathway interactions><Patients><Pb element><Peptides><Pharmaceutical Preparations><Pharmacodynamics><Pharmacokinetics><Phase><Phase I Study><Physiologic Availability><Pneumonia><Polymyxin E><Population><Pre IND FDA meeting><Pre-IND mtg><Proliferating><Protein Biosynthesis><Protocol><Protocols documentation><Pseudomonas aeruginosa><Pseudomonas pyocyanea><Pulmonary Diseases><Pulmonary Disorder><RNA><RNA Binding><RNA Gene Products><RNA bound><Rapid screening><Rat><Rats Mammals><Rattus><Renal function><Reporting><Research><Resistance><Resistance profile><Resistance to Multi-drug><Resistance to Multidrug><Resistance to Multiple Drug><Resistance to antibiotics><Resistant profile><Resistant to Multiple Drug><Resistant to antibiotics><Resistant to multi-drug><Resistant to multidrug><Ribonucleic Acid><Ribosomal Peptide Biosynthesis><Ribosomal Protein Biosynthesis><Ribosomal Protein Synthesis><Ribosomes><Risk><Risk-Benefit Assessment><Role><SARS><SARS coronavirus disease><SARS-CoV disease><SARS-CoV-2 associated death><SARS-CoV-2 associated fatality><SARS-CoV-2 associated mortality><SARS-CoV-2 death><SARS-CoV-2 fatality><SARS-CoV-2 induced death><SARS-CoV-2 induced fatality><SARS-CoV-2 induced mortality><SARS-CoV-2 mortality><SARS-CoV-2 related death><SARS-CoV-2 related fatality><SARS-CoV-2 related mortality><Sensory Hair><Sepsis><Serum><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome coronavirus disease><Severities><Societies><Solid><South Carolina><Structure><Superbug><Surgeon><Testing><Therapeutic><Therapeutic Index><Thigh><Thigh structure><Time><Tissue Growth><Toxic effect><Toxicities><United States><United States National Academy of Sciences><Universities><Urinary tract infection><Urinary tract infectious disease><Viral><Virus><Work><World Health Organization><Zebra Danio><Zebra Fish><Zebrafish><absorption><active followup><aminoglycoside ototoxicity><aminoglycoside-induced ototoxicity><anti-bacterial><anti-microbial agent><anti-microbial drug><anti-microbial resistant><anti-microbial resistant infection><antibiotic drug resistance><antibiotic resistant><antibiotic resistant infections><antimicrobial resistant infection><bacteria infection><bacteria pathogen><bacteria pneumonia><bacterial disease><bacterial pathogen><bacterial resistance><biofilm><blood infection><bloodstream infection><candidate identification><carbapenem resistance><carbapenem resistance in Enterobacteriaceae><carbapenem resistant><carbapenem-resistant Enterobacteriaceae><combat><corona virus><coronavirus disease 2019><coronavirus disease 2019 associated death><coronavirus disease 2019 associated fatality><coronavirus disease 2019 associated morbidity><coronavirus disease 2019 associated mortality><coronavirus disease 2019 death><coronavirus disease 2019 fatality><coronavirus disease 2019 induced death><coronavirus disease 2019 induced fatality><coronavirus disease 2019 induced morbidity><coronavirus disease 2019 induced mortality><coronavirus disease 2019 morbidity><coronavirus disease 2019 mortality><coronavirus disease 2019 related death><coronavirus disease 2019 related fatality><coronavirus disease 2019 related morbidity><coronavirus disease 2019 related mortality><coronavirus disease associated morbidity><coronavirus disease induced morbidity><coronavirus disease morbidity><coronavirus disease related morbidity><coronavirus disease-19><coronavirus disease-19 mortality><coronavirus infectious disease-19><cost><creativity><death due to COVID-19><death due to COVID19><death due to SARS-CoV-2><death due to coronavirus disease 2019><death due to severe acute respiratory syndrome coronavirus 2><death in COVID><death in COVID-19><death in SARS-CoV-2><death in coronavirus disease><death in coronavirus disease 2019><death in severe acute respiratory syndrome coronavirus 2><design><designing><developmental><disease of the lung><disorder of the lung><drug induced hearing impairment><drug induced hearing loss><drug resistant><drug/agent><ear hair cell><economic impact><efficacy study><excretion><extensive drug resistance><extensively drug resistant><extreme drug resistance><fatality due to COVID-19><fatality due to COVID19><fatality due to SARS-CoV-2><fatality due to coronavirus disease 2019><fatality due to severe acute respiratory syndrome coronavirus 2><flu virus pandemic><follow up><follow-up><followed up><followup><guinea pig model><heavy metal Pb><heavy metal lead><hospital days><hospital length of stay><hospital stay><improved><in vitro Organ Culturing><in vitro vertebrate organ culturing><in vivo><in vivo Model><influenza virus pandemic><inhibitor><innovate><innovation><innovative><institutional infection><interventional strategy><kidney function><lung disorder><method development><microorganism><mortality><mortality due to COVID-19><mortality due to COVID19><mortality due to SARS-CoV-2><mortality due to coronavirus disease 2019><mortality due to severe acute respiratory syndrome coronavirus 2><multi-drug resistant><multidisciplinary><multidrug resistant><new antibiotic class><new antibiotic type><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel antibiotic class><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><ontogeny><ototoxic><ototoxicity><pandemic flu><pandemic influenza><pandemic strain of influenza><pathogen><pathogenic bacteria><pathway><phase 1 study><pre-IND consultation><pre-IND discussion><pre-IND meeting><pre-Investigational New Drug meeting><pre-clinical><pre-clinical toxicity><preclinical><preclinical toxicity><priority pathogen><protein synthesis><pulmonary infections><rapid assay><rapid method><rapid technique><rapid test><rapid tests><resistance to Bacteria><resistance to Bacterial><resistance to Drug><resistance to anti-microbial><resistance to carbapenem><resistant><resistant to Bacteria><resistant to Bacterial><resistant to Drug><resistant to antimicrobial><resistant to carbapenem><screening><screenings><severe acute respiratory syndrome coronavirus 2 associated death><severe acute respiratory syndrome coronavirus 2 associated fatality><severe acute respiratory syndrome coronavirus 2 associated mortality><severe acute respiratory syndrome coronavirus 2 death><severe acute respiratory syndrome coronavirus 2 fatality><severe acute respiratory syndrome coronavirus 2 induced death><severe acute respiratory syndrome coronavirus 2 induced fatality><severe acute respiratory syndrome coronavirus 2 induced mortality><severe acute respiratory syndrome coronavirus 2 mortality><severe acute respiratory syndrome coronavirus 2 related death><severe acute respiratory syndrome coronavirus 2 related fatality><severe acute respiratory syndrome coronavirus 2 related mortality><small molecule><social role><standard of care><success><synergism><tigecycline><urinary infection>