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Principal Investigator: SCOTT J. HULTGREN
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $2,238,702
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ ABSTRACT:
Antibiotic-resistant bacterial infections that are no longer sensitive to our life saving antibiotic arsenal are a
looming catastrophe and like the recent COVID-19 crisis, will have dire consequences for human health if we
are not prepared. This proposal leverages basic science findings for development of antibiotic-sparing
medicines with impact on treatment for most pathogens designated threats to human health by the CDC.
Projects 1 and 2 target multi-drug resistant (MDR) Gram-negative pathogens that express adhesive pili
required for colonization and infection in the host habitats involved in acute and chronic/recurrent urinary tract
infections (UTIs) and catheter-associated UTIs (CAUTIs), including MDR Acinetobacter, carbapenem-resistant
Enterobacteriaceae (CRE) and extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae.
Project 2 expands on this list to include other Gram-negative pathogens of concern. Since UTIs account for
~10% of antibiotic use in humans, the development of antibiotic-sparing therapeutics will not only allow
treatment of antibiotic-resistant infections, but by reducing the use of current antibiotics, will decrease selective
pressures for resistance. Project 1 is focused on neutralizing bacterial pilus adhesins using glycomimetics
designed in CORE 1 and mAbs developed in CORE 2 that will block critical interactions between bacterial
adhesins and their host ligands. Glycomimetics have shown great promise in neutralizing chaperone/usher
pathway (CUP) adhesins in vivo to treat disease. For example, mannosides, which neutralize uropathogenic E.
coli (UPEC) adhesin FimH, are potent therapeutics for treating and preventing UTI, since FimH is required by
UPEC to colonize the bladder. In collaboration with GlaxoSmithKline a mannoside has been selected to
proceed into Phase 1a/1b clinical trials, thus validating the potential of this strategy. Therapeutic mAbs have
not yet been fully harnessed for treating infectious diseases. With antibiotic resistance on the rise, it is time to
apply this strategy. Project 1 will also target a sortase-assembled pilus adhesin of Gram-positive enterococci,
which causes CAUTIs and is often MDR. Project 2 will use similar tools to focus on the CUP machinery that
assembles the Gram-negative adhesins in Project 1 at the tip of pilus fibers. Project 3 will target all Gram-
positive species identified by the CDC as significant threats by furthering the development of GmPcides, a
novel family of ring-fused 2-pyridone compounds that are bactericidal against a broad spectrum of Gram-
positive species. The COREs will be fully integrated with the Scientific Projects providing computational and
synthetic medicinal chemistry in the development of small molecule therapeutics (CORE 1) and the application
of high throughput mAb generation against bacterial proteins (CORE 2). The combined knowledge, expertise
and successes of the Leaders of the Projects and Cores will lead to the development of antibiotic-sparing
therapeutics for treatment of the growing number of antibiotic-resistant pathogens to stave off the return to the
pre-antibiotic era when common infections were essentially untreatable.
Terms: <2(lH)-pyridinone><2-hydroxypyridine><2-pyridinone><2-pyridone><A baumanni><A baumannii><A. baumanni><A. baumannii><A.baumannii><Acinetobacter><Acinetobacter baumanni><Acinetobacter baumannii><Acute><Address><Adhesives><Advanced Development><Affect><Affinity><Animal Model><Animal Models and Related Studies><Antibiotic Agents><Antibiotic Drugs><Antibiotic Resistance><Antibiotic Therapy><Antibiotic Treatment><Antibiotics><Bacteria><Bacterial Adhesins><Bacterial Antibiotic Resistance><Bacterial Gene Products><Bacterial Gene Proteins><Bacterial Infections><Bacterial Proteins><Basic Research><Basic Science><Binding><Bladder><Bladder Urinary System><C diff><C difficile><C. diff><C. difficile><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><Calymmatobacterium><Carbapenem-resistant Acinetobacter><Cause of Death><Cell Body><Cells><Chaperone><Chemistry><Chlolincocin><Chlorlincocin><Chronic><Clindamycin><Clinical Treatment><Clinical Treatment Moab><Clostridioides difficile><Clostridium difficile><Coliform Bacilli><Collaborations><Communicable Diseases><Complex><Crystallization><D pneumoniae><D-Mannose><D. pneumoniae><Development><Diplococcus pneumoniae><Disease><Disorder><Donovania><Drug resistance><E coli Adhesin><E coli drug resistance><E coli drug resistant><E-Mycin><E. coli Adhesin><E. coli drug resistance><E. coli drug resistant><E.coli drug resistance><E.coli drug resistant><Enteric Bacteria><Enterobacteria><Enterobacteriaceae><Enterococcus><Ery-Tab><Eryc><Eryderm><Erythrocin><Erythromycin><Erythromycin A><Escherichia coli Adhesins><Escherichia coli drug resistance><Escherichia coli drug resistant><Experimental Therapies><Extended-spectrum beta-lactamase><Extended-spectrum β-lactamase><Family><Fiber><Funding><Generations><Goals><Gram-Negative Bacteria><Habitats><Health><Healthcare><Hospital Infections><Hospital acquired infection><Human><Ilotycin><Immunologist><Immunology><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Investigational Therapies><Investigational Treatments><Klebsiella><Knowledge><Lead><Life><Ligands><MAb Therapeutics><MDR Acinetobacter><MDR organism><MDR pathogen><MRSA><Mannopyranose><Mannopyranoside><Mannose><Mannosides><Mediating><Medicinal Chemistry><Medicine><Membrane><Methicillin Resistant S. Aureus><Microbiology><Miscellaneous Antibiotic><Modern Man><Molecular><Molecular Chaperones><Molecular Interaction><Monoclonal Antibodies><Multi-Drug Resistance><Multi-drug resistant Acinetobacter><Multidrug Resistance><Multidrug-resistant Acinetobacter><Multiple Anti-bacterial Drug Resistance><Multiple Anti-bacterial Drug Resistant><Multiple Bacterial Drug Resistance><Multiple Drug Resistance><Multiple Drug Resistant><NIH><National Institutes of Health><Nosocomial Infections><Pathogenesis><Pathogenicity><Pathway interactions><Patients><Pb element><Pediamycin><Permeability><Pharmaceutic Chemistry><Pharmaceutical Chemistry><Phase 1a/1b Clinical trial><Phase Ia/Ib Clinical Trial><Pilum><Pneumococcus><Process><Pyridinones><Pyridones><RP-Mycin><Receptor Protein><Recurrence><Recurrent><Resistance><Resistance to Multi-drug><Resistance to Multidrug><Resistance to Multiple Anti-bacterial Drug><Resistance to Multiple Drug><Resistance to antibiotics><Resistant S. 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Pneumoniae><resistant to Drug><resistant to E coli drug><resistant to E. coli drug><resistant to E.coli drug><resistant to Escherichia coli drug><school of medicine><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><small molecular inhibitor><small molecule><small molecule inhibitor><small molecule therapeutics><sortase><srtA gene product><structural biology><success><synergism><therapeutic mAbs><therapy development><tool><treatment development><trial regimen><trial treatment><urgent and serious threat><urgent or serious threat><urinary bladder><urinary infection><urinary tract catheter infection><vancomycin resistance enterococci><vancomycin resistance in enterococci>