Molecular docking, dynamics and in vitro analysis of multi-target inhibitors for Clostridioides difficile

TL;DR

This paper identifies new compounds that inhibit key proteins in Clostridioides difficile, a pathogen causing antibiotic-resistant infections, and validates their effectiveness in laboratory tests.

Contribution

The study reports for the first time the antimicrobial activity of five ZINC library compounds against Clostridioides difficile.

Findings

Five compounds from the ZINC library inhibit key C. difficile proteins and show antimicrobial activity in vitro.

The compounds were validated against four different C. difficile isolates.

Further testing is needed to develop these compounds into effective anti-clostridial drugs.

Abstract

The opportunistic pathogen, Clostridioides difficile owes its extreme pathogenicity for its ability to develop
antibiotic resistance and recurrent infections. The current antibiotics used for the treatment are showing declining sensitivity and
rising antibiotic resistance. Therefore, it is of interest to develop the anti-clostridial drugs to overcome these issues. Hence, we
have explored ZINC library to find the suitable lead compounds against five target proteins of C. difficile. Multistep
virtual screening is performed to find the suitable compounds that are checked for their stability using molecular dynamics and are
validated in vitro against C. difficile. In our study, five compounds viz., ZINC64969876, ZINC13641164,
ZINC13691348, ZINC5554596 and ZINC3894278 that inhibit HisC, Spo0A, PdcA, DAHP synthase and cyclic-di GMP proteins, respectively have
been identified. Further, these compounds were tested in vitro against four different isolates of
C. difficile and all of them were found to inhibit the pathogen. However, to use these compounds as anti-clostridial
drugs, further testing needs to be done. The selected compounds from our study are reported for the first time as antimicrobial agents
against C. difficile.

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