# Novel Strategies for Antibiotic Combinations to Combat Gram-negative Superbugs

> **NIH NIH R01** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2022 · $783,756

## Abstract

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 anti...

## Key facts

- **NIH application ID:** 10307517
- **Project number:** 5R01AI148560-03
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** Jurgen Bernd Bulitta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $783,756
- **Award type:** 5
- **Project period:** 2019-12-20 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10307517

## Citation

> US National Institutes of Health, RePORTER application 10307517, Novel Strategies for Antibiotic Combinations to Combat Gram-negative Superbugs (5R01AI148560-03). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10307517. Licensed CC0.

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