Broad-spectrum inhibitor of bacterial polyphosphate homeostasis attenuates virulence factors and helps reveal novel physiology of K. pneumoniae and A. baumannii

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Roberge, Nathan
polyphosphate , polyphosphate kinase , anti-virulence , virulence factors , Gram negative opportunistic pathogens
Acinetobacter baumannii and Klebsiella pneumoniae currently rank amongst the most antibiotic-resistant pathogens, responsible for numerous infections each year. In the wake of this continuing crisis, anti-virulence therapeutics targeting bacterial polyphosphate (polyP) homeostasis have been posited as an attractive alternative to traditional antibiotics. In this work, we show that the small molecule gallein, recently proven to have dual-specificity polyphosphate kinase (PPK) inhibition in Pseudomonas aeruginosa, also exhibits broad-spectrum PPK inhibition in other priority pathogens. Gallein treatment successfully attenuated virulence factors of K. pneumoniae and A. baumannii including biofilm formation, surface associated motility, and offered protection against A. baumannii challenge in a Caenorhabditis elegans model of infection. This was highlighted most importantly in the critically understudied A. baumannii, where gallein treatment mimicked a ppk1 knockout strain phenotype of a previously uncharacterized PPK1. Subsequent analysis revealed a rare instance of two functionally and phenotypically distinct PPK1 isoforms encoded by a single bacterium. Finally, gallein was administered to a defined microbial community comprising over 30 commensal species of the human gut microbiome, where microbial biodiversity was not adversely influenced. Together, these results further emphasize gallein as a promising avenue for the development of broad-spectrum anti-virulence therapeutics.
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