Project description:Antibiotic use can lead to expansion of multi-drug resistant pathobionts within the gut microbiome that can cause life-threatening infections. Selective alternatives to conventional antibiotics are in dire need. Here, we describe a Klebsiella PhageBank that enables the rapid design of antimicrobial bacteriophage cocktails to treat multi-drug resistant Klebsiella pneumoniae. Using a transposon library in carbapenem-resistant K. pneumoniae, we identified host factors required for phage infection in major Klebsiella phage families. Leveraging the diversity of the PhageBank and experimental evolution strategies, we formulated combinations of phages that minimize the occurrence of phage resistance in vitro. Optimized bacteriophage cocktails selectively suppressed the burden of multi-drug resistant K. pneumoniae in the mouse gut microbiome and drove bacterial populations to lose key virulence factors that act as phage receptors. Further, phage-mediated diversification of bacterial populations in the gut enabled co-evolution of phage variants with higher virulence and a broader host range. Altogether, the Klebsiella PhageBank represents a roadmap for both phage researchers and clinicians to enable phage therapy against a critical multidrug-resistant human pathogen.
Project description:Klebsiella pneumoniae has risen to prominence as a major threat to human health, with hypervirulent and drug-resistant lineages spreading globally. Given their antimicrobial resistant phenotypes, new therapies are required for the treatment of these infections, and bacteriophages (phages) that kill Klebsiella are being identified for use in phage therapy. In order to circumvent the evolution of phage-resistance taking hold the way that drug-resistance has, clear and considered actions are needed in selecting the phages that would be used in therapeutic cocktails. It is known that annotation of phage genomes is poor, potentially obscuring those phages with the most therapeutic potential. Here we show that phages isolated from infrequently sampled environments have features of therapeutic potential and developed a computational tool called STEP3 to understand the evolutionary features that distinguish the component parts of diverse phages, features that proved particularly suitable to detection of virion proteins with only distantly related homologies. These features were integrated into an ensemble framework to achieve a stable and robust prediction performance by STEP3. Proteomics-based analysis of two phages validated the prediction accuracy of STEP3 and revealed the virions contain component parts that include DNA-binding factors, otherwise unrecognizable capsule degradation enzymes and membrane translocation factors.
Project description:To investigate the role of outer membrane vesicles (OMVs) and related proteins in iron acquisition mechanism of hypervirulent Klebsiella pneumoniae (HVKP) and classic Klebsiella pneumoniae (cKP).
Project description:The Antibiotic Resistant Sepsis Pathogens Framework Initiative aims to develop a framework dataset of 5 sepsis pathogens (5 strains each) using an integrated application of genomic, transcriptomic, metabolomic and proteomic technologies. The pathogens included in this initiative are: Escherichia coli, Klebsiella pneumoniae complex, Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae. This submission pertains to strain BPH2900.
Project description:The Antibiotic Resistant Sepsis Pathogens Framework Initiative aims to develop a framework dataset of 5 sepsis pathogens (5 strains each) using an integrated application of genomic, transcriptomic, metabolomic and proteomic technologies. The pathogens included in this initiative are: Escherichia coli, Klebsiella pneumoniae complex, Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae. This submission pertains to strain BPH2947.
Project description:The Antibiotic Resistant Sepsis Pathogens Framework Initiative aims to develop a framework dataset of 5 sepsis pathogens (5 strains each) using an integrated application of genomic, transcriptomic, metabolomic and proteomic technologies. The pathogens included in this initiative are: Escherichia coli, Klebsiella pneumoniae complex, Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae. This submission pertains to strain BPH2986.
Project description:The Antibiotic Resistant Sepsis Pathogens Framework Initiative aims to develop a framework dataset of 5 sepsis pathogens (5 strains each) using an integrated application of genomic, transcriptomic, metabolomic and proteomic technologies. The pathogens included in this initiative are: Escherichia coli, Klebsiella pneumoniae complex, Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae. This submission pertains to strain 180-15.
Project description:The Antibiotic Resistant Sepsis Pathogens Framework Initiative aims to develop a framework dataset of 5 sepsis pathogens (5 strains each) using an integrated application of genomic, transcriptomic, metabolomic and proteomic technologies. The pathogens included in this initiative are: Escherichia coli, Klebsiella pneumoniae complex, Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae. This submission pertains to strain 180-2.
