Salicylanilide Analog Minimizes Relapse of Clostridioides difficile Infection in Mice

Abstract

Clostridioides difficile infection (CDI) causes serious and sometimes fatal symptoms like diarrhea and pseudomembranous colitis. Although antibiotics for CDI exist, they are either expensive or cause recurrence of the infection due to their altering the colonic microbiota, which is necessary to suppress the infection. Here, we leverage a class of known membrane-targeting compounds that we previously showed to have broad inhibitory activity across multiple Clostridioides difficile strains while preserving the microbiome to develop an efficacious agent. A new series of salicylanilides was synthesized, and the most potent analog was selected through an in vitro inhibitory assay to evaluate its pharmacokinetic parameters and potency in a CDI mouse model. The results revealed reduced recurrence of CDI and diminished disturbance of the microbiota in mice compared to standardof-care vancomycin, thus paving the way for novel therapy that can potentially target the cell membrane of C. difficile to minimize relapse in the recovering patient.

Assembly and Covalent Cross-Linking of an Amine-Functionalised Metal-Organic Cage

“…Unless otherwise stated, all chemicals were obtained from commercial sources and used as received. Compounds 4 and 5 were synthesised according to literature procedures ( Blake et al, 2020 ; Bloch et al, 2020 ). Triethyl amine (TEA) was distilled from KOH and stored under argon.…”

Investigation of Salicylanilides as Botulinum Toxin Antagonists

“…34 Successful mining of this library includes investigations for the treatment of Clotridioides dif f icile infection (CDI) in a CDI mouse model as well as reduction of SARS-CoV-2 replication in a rodent model. 32,33 Similar to previously studied salicylanilides, the mechanism is hypothesized to proceed via neutralization of endosomal pH to prevent release of toxin into the cytoplasm. 25,28,35 With the history of this salicylanilide library noted, we initiated a screen for BoNT/A inhibition in enzyme and cell assays examining SNAP-25 protection and studied their mechanism of action using fluorescence spectroscopy.…”

Salicylanilides Reduce SARS-CoV-2 Replication and Suppress Induction of Inflammatory Cytokines in a Rodent Model

“…The salicylanilide class’s protonophore properties 21 strongly rely on an acidic phenolic OH on the salicyl-ring and an amide proton for antimicrobial activity 22 although niclosamide’s amide proton seems to be a stronger contributor against viruses. 12 Based on our recent work examining salicylanilides for the treatment of Clostridioides difficile infections, 23 , 24 we explored the inductive effect on their protic substituents by enlisting a series of analogues ( 1 – 13 ) that carry functional groups ranging from strongly electron-donating (methoxy, 7 ) to electron-withdrawing (dinitro, 13 ) ( Table 1 ) in hopes of finding a more effective salicylanilide antiviral against COVID-19.…”

“…Notable is 11 ’s superiority at curbing viral replication without a major loss in viability (Table and Figure ) over niclosamide, which is currently in clinical trials as an oral anti-COVID-19 drug. , Salicylanilide 11 also carries less pharmacokinetic liability than niclosamide as it can be administered orally, yet with a 76% systemic bioavailability in mice in contrast to niclosamide’s 10% . Additionally, systemic toxicity from 11 was negligible at an oral twice-daily dose of 5 mg/kg for 5 days (Figure S2).…”

“…Additionally, systemic toxicity from 11 was negligible at an oral twice-daily dose of 5 mg/kg for 5 days (Figure S2). Moreover, in HEK 293T/17 human kidney cells, 11 presents much less toxicity than niclosamide . Finally, if endosomal acidification is the critical feature for salicylanilides to block SARS-CoV-2 cellular proliferation, then these molecules would be equally effective against recent emerging variants.…”