Sugar import suppresses Klebsiella pneumoniae Mucoidy in a cAMP-CRP-dependent manner

Hypervirulent Klebsiella pneumoniae (hvKp) causes severe invasive infections in community and hospital settings, often originating from gut colonization. Capsular polysaccharide (CPS) and its associated features are a key hvKp virulence factor. Altering CPS properties, such as mucoidy, in response to environmental cues enhances K. pneumoniae fitness. While several physical and nutrient cues influence mucoidy, the molecular mechanisms by which host-relevant signals, such as sugars, regulate mucoidy remain undefined. Here, we show that sugar import, not catabolism, broadly suppresses hvKp mucoidy through cAMP-CRP signaling and downregulation of the mucoidy regulator, rmpD. This sugar-dependent regulation is conserved across multiple hvKp strains. Although non-mucoid hvKp associate with gut mucin and epithelial cells at a greater frequency, both hypermucoid and non-mucoid states show reduced fitness for gut colonization. Our findings support that sugars are a key mucoidy regulatory cue and that the dynamic regulation of mucoidy contributes to efficient gut colonization by hvKp. Khadka et al. show that sugar import, not catabolism, suppresses mucoidy in hypervirulent Klebsiella pneumoniae via cAMP-CRP signaling. Dynamic regulation of this virulence trait promotes efficient gut colonization.