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Principal Investigator: DEV PRIYA ARYA
Organization: NUBAD, LLC
Fiscal Year: 2024
Award: $998,585
Funding agency: National Institute of Allergy and Infectious Diseases
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 influenza, SARS, COVID-19, 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. 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). Recent article by J. Gerberding, former CDC director states
“The patients at greatest risk from superbugs like CRE and other bacterial pathogens that 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).
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.
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
targeting MDR, XDR, and PDR bacterial infections. Targeting heavily conserved RNA sequences and 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. We will target specific rRNA single strands, which are conserved
across prokaryotes, essential for translation initiation but absent in eukaryotes, ensuring that a drug targeting
this sequence can function as a broad spectrum therapeutic. In the proposed work, we will construct sequence-
specific chemically modified rRNA targeting oligomers that can be effectively delivered inside the cell. Short RNA
will be exploited as target for synthetic molecules that inactivate the functioning of the ribosome, stopping
bacterial protein synthesis and causing bacterial death. NUBAD’s unique experimental approaches and
technologies will allow us to target rRNA combinations not previously explored for susceptibility against bacteria.
The work proposed is a multidisciplinary effort encompassing solid-phase organic synthesis, oligonucleotide
stability and delivery, RNA targeted screening, antimicrobial activity, ADME TOX, and in vivo efficacy studies
describes the development of sequence-specific cell permeable binders of rRNA. The success of the proposed
work would be a significant addition to currently available ribosome-specific approaches in drug development.
We propose using a small rRNA target sequence, heavily conserved in prokaryotes, to design conjugates that
can be employed to inhibit microbial growth, opening possibilities for developing sequence-specific RNA targeted
therapeutics. This work addresses an important world health issue, antimicrobial resistance, and presents
creative steps towards a novel solution to this problem.
Terms: <Abdominal Infection><Address><Amides><Amino Sugars><Aminoglycosides><Anti-Bacterial Agents><Antibiotic Agents><Antibiotic Drugs><Antibiotic Resistance><Antibiotics><Antimicrobial Resistance><Assay><Bacillus><Bacteria><Bacteria resistance><Bacteria resistant><Bacterial Gene Products><Bacterial Gene Proteins><Bacterial Infections><Bacterial Pneumonia><Bacterial Proteins><Bacterial resistant><Binding><Bioassay><Bioavailability><Biodistribution><Biological Assay><Biological Availability><Biology><Books><COVID-19><COVID-19 associated death><COVID-19 associated fatality><COVID-19 associated mortality><COVID-19 death><COVID-19 fatality><COVID-19 induced death><COVID-19 induced fatality><COVID-19 induced mortality><COVID-19 mortality><COVID-19 related death><COVID-19 related fatality><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 Body><Cell Wall><Cells><Cessation of life><Chemicals><Clinical><Coliform Bacilli><Colimycin><Colisticin><Colistin><Common Rat Strains><Communicable Diseases><Congresses><Coronaviridae><Coronavirus><Coronavirus Infectious Disease 2019><Coupled><Creativeness><Data><Death><Development><Disease><Disorder><Dose><Drug Design><Drug Interactions><Drug Targeting><Drug resistance><Drugs><E coli><E. coli><Elements><Ensure><Enteric Bacteria><Enterobacteria><Enterobacteriaceae><Epidemic><Escherichia coli><Eukaryota><Eukaryote><Face><Family><Follow-Up Studies><Followup Studies><GAR-936><Generalized Growth><Gram-Negative Bacteria><Grippe><Growth><Guinea Pigs><Guinea Pigs Mammals><H1N1><H1N1 Virus><Health Care Costs><Health Costs><Healthcare Costs><Hospital Infections><Hospital acquired infection><In Vitro><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Influenza><Influenza A Virus, H1N1 Subtype><Institute of Medicine><Institute of Medicine (U.S.)><Intervention><Intervention Strategies><Intra-abdominal><K pneumoniae><K. pneumoniae><Klebsiella pneumoniae><Knowledge><L Forms><Lead><Left><Length of Stay><Libraries><Link><Locales><Lung Diseases><Lung infections><M tuberculosis infection><M. tb infection><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MTB infection><Malaria><Medication><Membrane><Mice><Mice Mammals><Microbial Biofilms><Miscellaneous Antibiotic><Modeling><Molecular Interaction><Multi-Drug Resistance><Multidrug Resistance><Multiple Drug Resistance><Multiple Drug Resistant><Murine><Mus><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><NAS/IOM><National Academy of Sciences><Non-Polyadenylated RNA><Nosocomial Infections><Nucleic Acid Binding><Nucleic Acids><Number of Days in Hospital><Oligo><Oligonucleotides><Organic Synthesis><Paludism><Pathogenicity><Patients><Pb element><Peptide Nucleic Acids><Peptides><Permeability><Pharmaceutical Preparations><Phase><Physiologic Availability><Plasmodium Infections><Pneumonia><Polymyxin E><Pre IND FDA meeting><Pre-IND mtg><Predisposition><Prokaryotae><Prokaryotic Cells><Proliferating><Protein Biosynthesis><Protein Synthesis Antagonists><Protein Synthesis Inhibitors><Pulmonary Diseases><Pulmonary Disorder><RNA><RNA Binding><RNA Gene Products><RNA Sequences><RNA bound><RNA targeting drug><RNA targeting therapeutics><RNA-targeting therapy><Rapid screening><Rat><Rats Mammals><Rattus><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><Ribosomal RNA><Ribosomes><Risk><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><Sepsis><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome coronavirus disease><Severities><Societies><Solid><Specificity><Staphylococcal Infections><Staphylococcus infection><Structure><Superbug><Surgeon><Susceptibility><TB infection><Tail><Technology><Therapeutic><Thigh><Thigh structure><Time><Tissue Growth><Tobramycin><Tobrex><Toxic effect><Toxicities><Translation Initiation><Tuberculosis><United States><United States National Academy of Sciences><Urinary tract infection><Urinary tract infectious disease><Viral><Work><World Health><World Health Organization><aminosugar><anti-bacterial><anti-microbial><anti-microbial agent><anti-microbial drug><anti-microbial resistant><anti-microbial resistant infection><antibiotic drug resistance><antibiotic resistant><antibiotic resistant infections><antimicrobial><antimicrobial resistant infection><bacteria infection><bacteria pathogen><bacteria pneumonia><bacterial disease><bacterial pathogen><bacterial resistance><base><bases><biofilm><blood infection><bloodstream infection><candidate identification><carbapenem resistance in Enterobacteriaceae><carbapenem-resistant Enterobacteriaceae><combat><corona virus><coronavirus disease 2019><coronavirus disease 2019 associated death><coronavirus disease 2019 associated fatality><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 mortality><coronavirus disease 2019 mortality><coronavirus disease 2019 related death><coronavirus disease 2019 related fatality><coronavirus disease 2019 related mortality><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><disseminated TB><disseminated tuberculosis><drug development><drug induced hearing impairment><drug induced hearing loss><drug resistant><drug/agent><economic impact><efficacy study><extensive drug resistance><extensively drug resistant><extreme drug resistance><faces><facial><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><fighting><flu virus pandemic><heavy metal Pb><heavy metal lead><hospital days><hospital length of stay><hospital stay><improved><in vivo><infection due to Mycobacterium tuberculosis><influenza virus pandemic><inhibitor><innovate><innovation><innovative><institutional infection><interventional strategy><lung disorder><membrane structure><microbial><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><nucleic acid delivery><oligonucleotide delivery><oligos><ontogeny><ototoxic><ototoxicity><pandemic flu><pandemic influenza><pandemic strain of influenza><pathogen><pathogenic bacteria><pre-IND consultation><pre-IND discussion><pre-IND meeting><pre-Investigational New Drug meeting><pre-clinical><pre-clinical study><preclinical><preclinical study><prevent><preventing><priority pathogen><prokaryote><protein synthesis><pulmonary infections><rRNA><resistance to Bacteria><resistance to Bacterial><resistance to Drug><resistance to anti-microbial><resistant><resistant to Bacteria><resistant to Bacterial><resistant to Drug><resistant to antimicrobial><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><staph infections><success><synergism><targeted agent><tigecycline><tuberculosis infection><tuberculous spondyloarthropathy><uptake><urinary infection>