Cinnamic acid attenuates Klebsiella pneumoniae virulence by suppressing capsule biosynthesis

The widespread dissemination and serious clinical consequences of hypervirulent Klebsiella pneumoniae (hvKP), an encapsuled gram-negative pathogenic bacterium characterized by its specific virulence factor hypermucoviscosity (HMV), is becoming a concerning global public threat. In contrast to the common health care-associated infection of classical K. pneumoniae (cKp), hvKP is more virulent and capable of causing community-acquired invasive infections in healthy individuals, which mainly relies on the increased production of capsular polysaccharides (CPS) termed hypercapsule, and capsule-associated HMV. The indispensable role of capsule in mediating immune evasion, including resisting phagocytic engulfment and the killing of serum and host-derived antibacterial peptides, and other pathogenesis, renders it an attractive target for drug development against K. pneumoniae. Here, we identified the natural phenylpropanoid compound cinnamic acid (CA) as an effective inhibitor of K. pneumoniae capsule. The significant inhibition effect of CA on capsule biosynthesis was verified by both biochemical analysis and microscopic observation, and such drug action functioned in multiple K. pneumoniae strains. Mechanistically, CA hindered capsule biosynthesis by increasing bacterial carbon metabolism and consequently energy metabolism. Accordingly, hypercapsule-conferred hypermucoviscosity phenotype of hvKP was prominently impeded by CA. As a result, the cellular adherence and phagocytosis ratio, as well as serum killing and antibacterial peptide activity, were all improved by the inhibitor. In vivo, CA treatment significantly protected Galleria mellonella and mice from lethal hvKP infection. In conclusion, this study demonstrates that CA is a potent K. pneumoniae capsule inhibitor, which provides an alternative therapeutic strategy and active compound for K. pneumoniae infections.