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Principal Investigator: Jurgen Bernd Bulitta
Organization: STATE UNIVERSITY OF NEW YORK AT BUFFALO
Fiscal Year: 2024
Award: $751,348
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary/Abstract: Carbapenem-Resistant Enterobacteriaceae (CRE) have been classified as an
urgent public health threat in the US and around the globe. New Delhi Metallo-β-lactamases (NDM)
producing CRE are particularly concerning as they have rapidly spread worldwide and can efficiently co-
exist with a plethora of Gram-negative resistance determinants including Extended Spectrum β-lactamases
(ESBLs), carbapenemases, and polymyxin resistance genes. We have reported the first US case of
polymyxin- and carbapenem-resistant E. coli producing New Delhi Metallo-beta-lactamase (NDM-5)
together with mobile colistin resistance (MCR-1) in a patient. The recent report of pan-drug-resistant (PDR),
K. pneumoniae (NDM-1, ESBLs, and polymyxin resistance determinants), from a patient in Nevada further
highlights that it may be only a matter of time until hospitals in the US and worldwide face an outbreak of
these Gram-negative ‘superbugs’. It is critical to prepare therapeutics for the future occurrence of NDM
strains which harbor a diverse array of resistance determinants. Our Central Hypothesis is that rationally
optimized antibiotic combination dosing strategies will achieve extensive killing and prevent emergence of
resistance against of NDM-producing Enterobactericeae. Our preliminary studies provide compelling
evidence in support of our innovative combinations. We established the first highly efficient cassette assay
to assess target site penetration of β-lactams in the presence of polymyxins, the first dataset on β-lactam
receptor binding in K. pneumoniae, and show that new 4-drug combination regimens eradicated NDM and
ESBL co-producing K. pneumoniae and prevented resistance. In Aim 1, we will create genetically
engineered strains, as well as assess the target site penetration and receptor binding of β-lactam antibiotics
and β-lactamase inhibitors, and the enhanced penetration in presence of polymyxins. In Aim 2, in vitro
pharmacokinetic/pharmacodynamics models, including the dynamic Hollow Fiber Infection Model, will
evaluate optimized dosing strategies for 3- and 4-drug combinations by profiling the time course of bacterial
killing, suppression of resistance, and persister eradication. Genomics and transcriptomics will be utilized to
understand why monotherapies and non-optimized combinations failed with resistance. In Aim 3, our latest
Quantitative and Systems Pharmacology (QSP) modelling approach will guide translation across all
experimental tiers. Prospective validation of these novel optimal combination dosing strategies will be
completed in murine pneumonia models with an intact and impaired immune system. This will yield
innovative combination dosage regimens against pandrug-resistant CRE that can suppress resistance.
Thus, this project will address an urgent, global medical need. This project will provide the first
mechanistically informed, rationally optimized and prospectively validated combination dosing strategies of
available antibiotics against resistant Gram-negatives that will be ready for testing in future clinical trials.
Terms: <Abdominal Infection><Affinity><Antibiotic Agents><Antibiotic Drug Combinations><Antibiotic Drugs><Antibiotics><Assay><Az-threonam><Azactam><Azthreonam><Aztreonam><Bacteria><Binding><Binding Proteins><Bioassay><Biological Assay><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Carbapenems><Cas nuclease technology><Ccra beta-lactamase><Ceftazidime><Cell Membrane Permeability><Chromosomes><Classification><Clinic><Clinical><Clinical Trials><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Colistin resistant><Combined Antibiotics><Data><Data Set><Disease Outbreaks><Dose><Drug Combinations><Drug Kinetics><Drug resistance><Drugs><E coli><E. coli><Engineering><Escherichia coli><Extended-spectrum beta-lactamase><Extended-spectrum β-lactamase><Face><Fiber><Future><G24 protein><Genetic Alteration><Genetic Change><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Genetic defect><Genomics><Goals><Health><Hospitals><Human><Immune system><Immunocompetent><Impairment><In Vitro><Infection><Intra-abdominal><K pneumoniae><K. pneumoniae><Klebsiella pneumoniae><Ligand Binding Protein><Ligand Binding Protein Gene><Mediating><Medical><Medication><Membrane><Mice><Mice Mammals><Miscellaneous Antibiotic><Modeling><Modern Man><Molecular><Molecular Interaction><Murine><Mus><Mutation><Nevada><Outbreaks><Patients><Penetration><Penicillin-Binding Proteins><Permeability><Pharmaceutical Preparations><Pharmacokinetics><Pharmacology><Plasmids><Polymyxin B><Polymyxin Resistance><Polymyxin Resistant><Polymyxins><Prevention><Protein Binding><Public Health><Receptor Protein><Recombinant DNA Technology><Regimen><Reporting><Resistance><Safety><Sepsis><Site><Superbug><System><Systematics><Techniques><Testing><Therapeutic><Time><Translations><Urinary tract><VDAC1><VDAC1 gene><Validation><beta lactam antibiotic><beta lactam hydrolase><beta-Lactamase><beta-Lactamhydrolase><beta-Lactams><blood infection><bloodstream infection><bound protein><carbapenem resistance><carbapenem resistance in Enterobacteriaceae><carbapenem resistant><carbapenem-resistant Enterobacteriaceae><carbapenemase><colistin resistance><combat><data integration><design><designing><dosage><drug resistant><drug/agent><faces><facial><genetically engineered><genome mutation><global health><immune competent><improved><inhibitor><innovate><innovation><innovative><insight><membrane permeability><membrane structure><mortality><new approaches><novel><novel approaches><novel strategies><novel strategy><pathogen><pharmacodynamic model><pneumonia model><pneumonia models><pore forming protein><porin><prevent><preventing><prospective><receptor><receptor binding><receptor bound><resistance gene><resistance in K pneumoniae><resistance in K. pneumoniae><resistance in Klebsiella pneumoniae><resistance locus><resistance mechanism><resistance strain><resistance to Drug><resistance to carbapenem><resistance to colistin><resistance to polymyxin><resistant><resistant K pneumoniae><resistant K. pneumoniae><resistant Klebsiella pneumoniae><resistant gene><resistant mechanism><resistant strain><resistant to Drug><resistant to carbapenem><resistant to colistin><resistant to polymyxin><respiratory><transcriptomics><translation><validations><β lactam antibiotic><β-Lactamase><β-Lactams>