Discovery of anti-mucoviscous activity of rifampicin and its potential as a candidate anti-virulence agent against hypervirulent Klebsiella pneumoniae.

Abstract

A recent increase in the incidence of hypervirulent Klebsiella pneumoniae (hvKP) infections, especially those caused by a sublineage of the clonal group CG23 (CG23-I), is raising serious health concerns worldwide. The high virulence of hvKP is, at least in part, attributed to the overproduction of capsular polysaccharide (CPS), which is triggered by a positive regulator of capsular polysaccharide synthesis (cps) genes, named RmpA. Although extensive research has been conducted on the mechanisms of hvKP virulence, no study has focused on the development of anti-virulence therapeutics. Here, we attempted to identify and validate an antimicrobial agent able to suppress hvKP hypermucoviscosity. We tested 18 commercially available agents including β-lactams, quinolones, and aminoglycosides. We found that rifampicin (RFP) has a strong anti-mucoviscous activity against CG23-I hvKP that is exerted even at subinhibitory concentrations. Polysaccharide extracts from hvKP showed substantially lowered viscosity when cells were grown with RFP. Moreover, microscopic observations demonstrated that RFP treatment results in a drastic reduction in the thickness of the CPS layer around hvKP cells. RFP treatment decreased transcript levels of rmpA and rmpA-regulated cps genes, indicating that RFP suppresses mucoviscosity of hvKP through inhibition of rmpA transcription. Our data suggest that RFP may serve as a potential anti-virulence agent for refractory infection by hvKP.