Novel Indole-Based Hydrazones as Potent Inhibitors of the α-class Carbonic Anhydrase from Pathogenic Bacterium Vibrio cholerae.

Kübra Demir-Yazıcı,Claudiu T Supuran,Andrea Angeli,Atilla Akdemir,Özlen Güzel-Akdemir

doi:10.3390/ijms21093131

Abstract

Due to the increasing resistance of currently used antimicrobial drugs, there is an urgent problem for the treatment of cholera disease, selective inhibition of the α-class carbonic anhydrases (CA, EC 4.2.1.1) from the pathogenic bacterium Vibrio cholerae (VcCA) presents an alternative therapeutic target. In this study, a series of hydrazone derivatives, carrying the 2-(hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide scaffold, have been evaluated as inhibitors of the VcCA with molecular modeling studies. The results suggest that these compounds may bind to the active site of VcCA. To verify this, VcCA enzyme inhibition studies were performed and as predicted most of the tested compounds displayed potent inhibitory activities against VcCA with three compounds showing KI values lower than 30 nM. In addition, all these compounds showed selectivity for VcCA and the off-targets hCA I and II.

Highlights

Cholera is an acute diarrheal infection caused by pathogenic Gram-negative comma-shaped bacterium Vibrio cholerae and spreads by the ingestion of contaminated water or food
No crystal structure exists of the Vibrio cholerae α-carbonic anhydrase enzymes (CA) enzyme (VcCA; Uniprot: A0A0X1L2C8)
A BLAST search for protein crystal structures with similar sequences as the VcCA sequence was performed. This identified the α-CA from Photobacterium profundum (PpCA; pdb: 5hpj; 1.5 Å) as a template for the construction of VcCA homology models

Summary

Introduction

Cholera is an acute diarrheal infection caused by pathogenic Gram-negative comma-shaped bacterium Vibrio cholerae and spreads by the ingestion of contaminated water or food. Vibrio cholerae is divided into 200 serogroups based on O antigen, but only the O1 or O139 serogroups are responsible for epidemic or pandemic cholera [1,2,3]. This highly virulent bacteria causes characteristic rice-water stool, typical clinical symptoms like dehydration, hypovolemic shock, acidosis, and if not well-treated leads to death [4,5]. There are roughly 1.3–4.0 million cases, and 21,000–143,000 deaths worldwide due to cholera and the last estimated global burden of cholera was approximately 1.2 million cases and 5654 deaths in 34 endemic countries, reported in 2017 by the World Health Organization (WHO) [6,7]. Cholera continues to be a global public health problem that often affects the nations with lower economic status and indicates the inequality and lack of social development between the countries [10,11]

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Conclusion