Suppressed virulence and enhanced antibiotic efficacy of madecassic acid as a potent quorum sensing inhibitor against Klebsiellapneumoniae.

Abstract

Drug-resistant Klebsiella pneumoniae (K. pneumoniae) represents a formidable clinical challenge. Targeting its quorum sensing (QS) system has emerged as a promising anti-virulence strategy to combat antibiotic resistance. In this study, eighteen pentacyclic triterpenes (PTs) were screened for their in vitro activity against K. pneumoniae. Among them, madecassic acid (PT-5) exhibited a negligible bactericidal effect but significantly suppressed key virulence traits in a highly virulent, multidrug-resistant K. pneumoniae strain (KP31). These suppressed traits included biofilm formation, AI-2 production, capsular polysaccharide synthesis, and swarming motility, identifying PT-5 as a potent quorum sensing inhibitor with anti-virulence properties. Moreover, PT-5 demonstrated a synergistic effect at a subinhibitory concentration (32 μg/mL) when combined with conventional antibiotics, enhancing the bactericidal activity of kanamycin by 31 %, streptomycin by 29 %, azithromycin by 24 %, and chloramphenicol by 24 %. In a Galleria mellonella larval infection model, PT-5 in combination with kanamycin markedly boosted larval survival to 60 %, compared with 20 % for kanamycin monotherapy. Quantitative PCR analysis further revealed that PT-5 significantly downregulated the expression of key QS-related genes (luxS, sdiA, lsrK) and major virulence-associated genes (wbbM, wzm, pgaA, mrkA) in KP31. In summary, PT-5 acts as an effective QS inhibitor that suppresses virulence and enhances antibiotic efficacy, representing a promising combinational therapy against drug-resistant K. pneumoniae.