Methods for treatment of clostridium difficile infections

Abstract

In this study, we capitalized on the antimicrobial property and low oral bioavailability of known salicylanilide anthelmintics (closantel, rafoxanide, niclosamide, oxyclozanide) to target the gut pathogen. The anthelmintics displayed excellent potency against C. difficile strains 630 and 4118 (with MIC values as low as 0.06-0.13 μg/mL for rafoxanide) via a membrane depolarization mechanism. Interestingly, closantel, rafoxanide and compound 8 were bactericidal against logarithmic- and stationary-phase cultures of the BI/NAP1/027 strain 4118. Further evaluation of the salicylanilides showed their preferential activity against Gram-positive over Gram-negative bacteria. Moreover, the salicylanilides were non-hemolytic and were non-toxic to mammalian cell lines HepG2 and HEK 293T/17 within the range of their in vitro MICs and MBCs. The salicylanilide anthelmintics exhibit desirable bactericidal and pharmacokinetic properties and are amenable to repositioning as anti-C. difficile agents.

1 . A method of treatment of a  Clostridium difficile  infection in a mammal, comprising administering to the mammal an effective dose of a compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein X is halo or H, provided at least one X is halo, wherein the ring bearing X is optionally further substituted with halo; 
         wherein Ar is benzyl, naphthyl, or indanyl, unsubstituted or independently substituted with one or more halo, (C1-C4)alkyl, cyano, or nitro groups. 
       
     
     
         2 . The method of  claim 1 , wherein X is chloro or iodo. 
     
     
         3 . The method of  claim 1 , wherein Ar is substituted with halo or (C1-C4)alkyl, or both. 
     
     
         4 . (canceled) 
     
     
         5 . A compound having the formula: