Design and implementation of effective cOmbination of Phages and Antibiotics for improved TheRApy protocols against KLEbsiella pneumoniae
( KLEOPATRA )
Klebsiella pneumoniae is a critical pathogen (WHO priority 1) that displays pan-resistance against prevalent antibiotics. Moreover, capsular polysaccharides (K-antigen) are the key virulence factor protecting this bacterium against the human immune system response & harsh environments. The KLEOPATRA consortium is a multidisciplinary team of clinicians, microbiologists, bioinformaticians, focusing on the use of (bacterio)phages and their components (capsule depolymerases, CD) as sustainable combinations with antibiotics (AB). As natural predators of bacteria, some phages specifically recognize and target the K-antigen as a receptor for infection. In this proposal, we introduce the concept of K-sensitization, which utilizes capsule-specific (CS) phages and their CDs to drive bacteria towards capsule depletion. These (1) resensitize bacteria to the AB treatment, (2) sensitize Klebsiella to the host defence system, and (3) make strains susceptible to capsule-independent (CI) phages recognizing receptors hidden beneath the capsule layer. The envisioned K-sensitization preclinical proof-of-concept aims to develop a synergistic phage therapy/antibiotic treatment protocol against encapsulated pathogens that helps preserve the commensal microbiome diversity. The approach is supported by pheno- and genotype analyses of prevalent clinical & environmental isolates. Furthermore, the design of AB/phage/CD cocktails will be driven by tailored diagnostics tools, a unique phage production approach of dedicated phage banks and data-powered mathematical models for optimal synergy.
- 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)
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.