Rapid design of bacteriophage cocktails to suppress the burden and virulence of gut-resident carbapenem-resistant Klebsiella pneumoniae.

Antibiotic use can lead to the 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 for the tailored design of bacteriophage cocktails to treat multi-drug-resistant Klebsiella pneumoniae. Using a transposon library in carbapenem-resistant K. pneumoniae , we identify host factors required for phage infection in major Klebsiella phage families. Leveraging the diversity of the PhageBank, we formulate phage combinations that eliminate K. pneumoniae with minimal phage resistance. Optimized cocktails selectively suppress the burden of K. pneumoniae in the mouse gut and drive the loss of key virulence factors that act as phage receptors. Phage-mediated diversification of bacterial populations in the gut leads to co-evolution of phage variants with higher virulence and broader host range. Altogether, the Klebsiella PhageBank charts a roadmap for phage therapy against a critical multidrug-resistant human pathogen. [Display omitted] • A diverse Klebsiella PhageBank is used to construct cocktails that prevent resistance • Host factors required by the taxonomically diverse Klebsiella phage are mapped • Phage cocktails suppress gut K. pneumoniae in mice and select for capsule loss • Antagonistic co-evolution drives phage and bacterial diversification in the gut Leveraging a well-characterized library of bacteriophages, Rotman et al. demonstrate that cocktails of phages can suppress the burden of carbapenem-resistant Klebsiella pneumoniae in the mouse gut microbiome. In the gut, phage-bacterial interactions select for bacterial mutants with lessened virulence and phage variants with broadened host range. [ABSTRACT FROM AUTHOR]