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KLEOPATRA project details

PUBLIC ABSTRACT

The multidrug-resistant bacteria Klebsiella pneumoniae represents a critically emerging pathogen that confounds treatment in a clinical setting. This is due to their pan-resistance to antibiotics and specific biological traits, including a protective capsule, that makes it insensitive to the human immune system. Bacterial viruses, also called (bacterio)phages are the natural predators of bacteria and our previous research has identified phages that overcome this protective barrier and resensitize these bacteria to an immune as well as response antibiotic treatment. In this proposal, we will apply the concept of “K-sensitization” which uses these phages and their enzymes (capsule depolymerases) to strip the protective capsules from prevalent K. pneumoniae strains and provide a proof-of-concept of how phages/depolymerases act synergistically to antibiotic treatment. Besides the development of a protocol for compassionate phage therapy against these encapsulated pathogens, we will comprehensively analyze the prevalent K. pneumoniae circulating in human & animal reservoirs as well as environmental ecosystems. This in turn will lead to the establishment of tailored phage banks and associated diagnostics tools, supported by computational models to ensure rationally designed phage therapy cocktails for antibiotic/phage/enzyme combination treatments. In this way, the KLEOPATRA consortium aims to contribute to improving the treatment of this critical WHO priority 1 pathogen within a ‘One Health’ setting.

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RESEARCH PROJECT PARTNERS

  • Zuzanna Drulis-Kawa, University of Wroclaw, Poland (Coordinator)

  • Rob Lavigne, Katholieke Universiteit Leuven, Belgium (Partner)

  • Regis Tournebize, Sorbonne Université, France (Partner)

  • Joachim J. Bugert, Bundeswehr Institute of Microbiology, Germany (Partner)

  • Jens Andre Hammerl, German Federal Institute For Risk Assessment, Germany (Partner)

  • Ronen Hazan, Hebrew University of Jerusalem, Israel (Partner)

  • Kilian Vogele, INVITRIS SME, Germany (Partner)

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Main aims of KLEOPATRA project:

  1. Development of a protocol for K-sensitization phage therapy against encapsulated pathogens, implemented towards K. pneumoniae (WP1-6)

  2. Monitoring of K. pneumoniae prevalence, drug resistance and virulence in ONE HEALTH settings (WP1)

  3. Establishing a ONE HEALTH Klebsiella phage bank classified towards specificity groups (WP2)

  4. Development of phage-inspired rapid K-typing protocol and a low threshold phagogram for Klebsiella spp. as proof of concept for encapsulated pathogens (WP3)

  5. The development of new mathematical models for optimisation of antimicrobial combinations in treatment protocols and companion diagnostics for K. pneumoniae, as proof of concept for encapsulated pathogens – in silico phagogram (WP5)

  6. Implementation of an innovative, low-endotoxin phage production method (WP2)

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Call

2022 - Disrupting drug resistance using innovative design

 

 

 

KLEOPATRA work packages

WP 1
ONE HEALTH
K. pneumoniae strains monitoring

  1. KP from clinics - sample collection

  2. KP prevalence in animal / environmental settings - samples collection

  3. KP phenotypic and antibiotics sensivity testing

  4. WGS analysis of KP isolates

WP 2
Elaboration of phage preparations

  1. WGS analysis of phages

  2. phage serotype specificity / isolation of new phages

  3. purification and stability of phage products

WP 3
Application of CDs in thephage-host interplay

  1. CDs detection and production as recombinant proteins

  2. application of CDs for novel protocols of K serotype detection

  3. application of CDs for novel phagogram protocols

  4. novel combinations of AB / phage / CD and resistance emergency analyses

  5. WGS analysis of bacterial resistant variants from 3.4

WP 4
In vivo (mouse model) evaluation of
most top AB /phage /CD combinations

  1.  LD50 inoculum evaluation in model of pneumonia

  2. antibacterials activity testing in model of pnemumonia

  3. phenotypic and WGS analyses of bacterial resistant variants from 4.2

WP 5
The development of new mathematical models for optimisation of antimicrobial combinations in treatment protocols and companion diagnostics

  1.  mathematical model for phage-host interactions and phage cocktail design

  2. KLEOPATRA software for the rational design of AB / phage / CD combinations

WP 6
Project management and dissemination

  1. Project coordination

  2. Data Management Plan

  3. Dissemination and Communication Plan

  4. External Advisory Board

  5. Intellectual Property Management

KLEOPATRA impact pathway

KLEOPATRA impact pathway
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