Isoferulic acid facilitates effective clearance of hypervirulent Klebsiella pneumoniae through targeting capsule

Hypervirulent Klebsiella pneumoniae (hvKP) poses an alarming threat in clinical settings and global public health owing to its high pathogenicity, epidemic success and rapid development of drug resistance, especially the emergence of carbapenem-resistant lineages (CR-hvKP). With the decline of the “last resort” antibiotic class and the decreasing efficacy of first-line antibiotics, innovative alternative therapeutics are urgently needed. Capsule, an essential virulence determinant, is a major cause of the enhanced pathogenicity of hvKP and represents an attractive drug target to prevent the devastating clinical outcomes caused by hvKP infection. Here, we identified isoferulic acid (IFA), a natural phenolic acid compound widely present in traditional herbal medicines, as a potent broad-spectrum K . pneumoniae capsule inhibitor that suppresses capsule polysaccharide synthesis by increasing the energy status of bacteria. In this way, IFA remarkably reduced capsule thickness and impaired hypercapsule-associated hypermucoviscosity phenotype (HMV), thereby significantly sensitizing hvKP to complement-mediated bacterial killing and accelerating host cell adhesion and phagocytosis. Consequently, IFA facilitated effective bacterial clearance and thus remarkably protected mice from lethal hvKP infection, as evidenced by limited bacterial dissemination and a significant improvement in survival rate. In conclusion, this work promotes the development of a capsule-targeted alternative therapeutic strategy for the use of the promising candidate IFA as an intervention to curb hvKP infection, particularly drug-resistant cases. Hypervirulent Klebsiella pneumoniae (hvKP) is becoming an imminent threat to public health because of the constant emergence of drug resistance and its devastating clinical outcomes. Meanwhile, the both notorious phenotypes are integrated to create carbapenem-resistant and hypervirulent K . pneumoniae (CR-hvKP), which leads to a scarcity of effective treatments. Therefore, there is an increasing urgent need for new therapeutics other than antibiotics. The indispensable role of capsule in immune evasion and pathogenesis renders it a promising target for developing novel alternative strategies to combat hvKP infections. In this study, we identified the small natural compound isoferulic acid (IFA) as a potent broad-spectrum inhibitor of K . pneumoniae capsule. Hypercapsule-associated hypermucoviscosity (HMV), a characteristic phenotype that has been shown to play a distinct and critical role in the pathogenesis of hvKP, is significantly impaired by IFA. RNA-seq analysis revealed that IFA interferes with the biosynthesis of capsule polysaccharide through altering bacterial metabolism status. Consequently, IFA sensitizes hvKP to serum killing and impedes capsule- and HMV-mediated resistance to adherence and phagocytosis. In vivo, IFA treatment facilitates effective host clearance and thereby systemically protects mice against hvKP infection. Our research sheds light on the development of capsule-targeted drug and provides an effective lead compound that may contribute to the management of hvKP infections as an intervention.