Reprofiled anthelmintics abate hypervirulent stationary-phase Clostridium difficile

作者：Gooyit Major; Janda Kim D

来源：Scientific Reports, 2016, 6(1): 33642.

DOI：10.1038/srep33642

<jats:title>Abstract</jats:title><jats:p>Prolonged use of broad-spectrum antibiotics disrupts the indigenous gut microbiota, which consequently enables toxigenic <jats:italic>Clostridium difficile</jats:italic> species to proliferate and cause infection. The burden of <jats:italic>C. difficile</jats:italic> infections was exacerbated with the outbreak of hypervirulent strains that produce copious amounts of enterotoxins and spores. In recent past, membrane-active agents have generated a surge of interest due to their bactericidal property with a low propensity for resistance. In this study, we capitalized on the antimicrobial property and low oral bioavailability of salicylanilide anthelmintics (closantel, rafoxanide, niclosamide, oxyclozanide) to target the gut pathogen. By broth microdilution techniques, we determined the MIC values of the anthelmintics against 16 <jats:italic>C. difficile</jats:italic> isolates of defined PCR-ribotype. The anthelmintics broadly inhibited <jats:italic>C. difficile</jats:italic> growth <jats:italic>in vitro</jats:italic> via a membrane depolarization mechanism. Interestingly, the salicylanilides were bactericidal against logarithmic- and stationary-phase cultures of the BI/NAP1/027 strain 4118. The salicylanilides were poorly active against select gut commensals (<jats:italic>Bacteroides</jats:italic>, <jats:italic>Bifidobacterium</jats:italic> and <jats:italic>Lactobacillus</jats:italic> species) and were non-hemolytic and non-toxic to mammalian cell lines HepG2 and HEK 293T/17 within the range of their <jats:italic>in vitro</jats:italic> MICs and MBCs. The salicylanilide anthelmintics exhibit desirable properties for repositioning as anti-<jats:italic>C. difficile</jats:italic> agents.</jats:p>

• 出版日期2016-9-16