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Bacteriophage inhibition of antibiotic-resistant pathogenic microbes and founding for novel therapeutic strategies

Project description

Profiling a mysterious natural 'warrior' to counter antimicrobial resistance

Complex battles between single-celled organisms – bacteria and the viruses that 'eat' them (bacteriophages) – take place all around us largely unbeknownst to the average person. As antimicrobial resistance creates an ever-growing challenge to public health, harnessing these natural bacterial killers is a promising route to new therapeutics. The problem is that, although bacteriophages are the most abundant organisms in the biosphere, we have isolated very few of them and have very little idea about how they work. All that is about to change thanks to the EU-funded PHARMS project. Scientists have ambitious plans to find all possible phages of a resistant bacterial isolate, characterise the mechanisms of action, and use the new-found knowledge to design a toolkit of phage-based therapies.

Objective

Emergence of antimicrobial resistance (AMR) is a grand scientific challenge of our time that has killed more than 700,000 people worldwide. Phage therapy, a promising complement to antibiotics, utilizes viruses of bacteria (bacteriophages) or phage-derived inhibitors as natural ways to fight AMR. The main obstacles in the clinical application of phage-based AMR therapy are the limited number of phage isolates and the unknown molecular mechanisms of phage-delivered bactericidal action. Building on the recent advances of my group in high-throughput, culture-independent but host-targeted methodologies, PHARMS aims to deploy a revolutionary approach: to screen for all possible phages of a resistant bacterial isolate, characterize multiple lines of their bactericidal functions, and use this information for the design of a whole battery of phage-based therapies that employ multifaceted modes of action.

Using an interdisciplinary research plan, PHARMS will discover phage-specific bactericidal action modes at all possible levels ranging from nucleotide sequence and transcription to translation, in order to elucidate the molecular mechanisms driving phage-mediated inhibition of AMR Acinetobacter baumannii, Helicobacter pylori, & Haemophilus influenzae (WP1). These discoveries, together with novel synthetic biology tools, will enable us to engineer an array of phage vectors that mimic phage-deployed bactericidal modes discovered under WP1, including transport of alien genes to deliver bactericidal effects (WP2). PHARMS will provide molecular confirmation and in vitro & in vivo validation of the functions of phage-encoded bactericidal peptides and enzymes (WP3). By elucidating universal and specific mechanisms of phage-delivered inhibition of AMR pathogens, PHARMS is positioned to provide the rational framework for the design of novel therapeutic strategies aimed at treating common and life-threatening infectious diseases.

Keywords

Host institution

HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUNGSZENTRUM FUER GESUNDHEIT UND UMWELT GMBH
Net EU contribution
€ 1 499 650,00
Address
INGOLSTADTER LANDSTRASSE 1
85764 Neuherberg
Germany

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Region
Bayern Oberbayern München, Landkreis
Activity type
Research Organisations
Links
Total cost
€ 1 499 650,00

Beneficiaries (1)