A Microbiological, Toxicological, and Biochemical Study of the Effects of Fucoxanthin, a Marine Carotenoid, on Mycobacterium tuberculosis and the Enzymes Implicated in Its Cell Wall: A Link Between Mycobacterial Infection and Autoimmune Diseases.

Miroslava Šudomová,Ioana Berindan-Neagoe,Mohammad Shariati,Seyed Nabavi,Javier Echeverría,Sherif Hassan

doi:10.3390/md17110641

Abstract

This study explored the antitubercular properties of fucoxanthin, a marine carotenoid, against clinical isolates of Mycobacterium tuberculosis (Mtb). Two vital enzymes involved in Mtb cell wall biosynthesis, UDP-galactopyranose mutase (UGM) and arylamine-N-acetyltransferase (TBNAT), were selected as drug targets to reveal the mechanism underlying the antitubercular effect of fucoxanthin. The obtained results showed that fucoxanthin showed a clear bacteriostatic action against the all Mtb strains tested, with minimum inhibitory concentrations (MIC) ranging from 2.8 to 4.1 µM, along with a good degree of selectivity index (ranging from 6.1 to 8.9) based on cellular toxicity evaluation compared with standard drug isoniazid (INH). The potent inhibitory actions of fucoxanthin and standard uridine-5’-diphosphate against UGM were recorded to be 98.2% and 99.2%, respectively. TBNAT was potently inactivated by fucoxanthin (half maximal inhibitory concentration (IC50) = 4.8 µM; 99.1% inhibition) as compared to INH (IC50 = 5.9 µM; 97.4% inhibition). Further, molecular docking approaches were achieved to endorse and rationalize the biological findings along with envisaging structure-activity relationships. Since the clinical evidence of the last decade has confirmed the correlation between bacterial infections and autoimmune diseases, in this study we have discussed the linkage between infection with Mtb and autoimmune diseases based on previous clinical observations and animal studies. In conclusion, we propose that fucoxanthin could demonstrate great therapeutic value for the treatment of tuberculosis by acting on multiple targets through a bacteriostatic effect as well as by inhibiting UGM and TBNAT. Such outcomes may lead to avoiding or decreasing the susceptibility to autoimmune diseases associated with Mtb infection in a genetically susceptible host.

Highlights

Mycobacterium tuberculosis (Mtb) is a pathogenic microorganism that targets alveolar macrophages and induces tuberculosis in humans and animals [1]
The antimicrobial activity of fucoxanthin and the standard drug isoniazid (INH) was assessed by microdilution assay against ten clinical isolates of Mtb along with a reference strain
TBNAT as crucial drug targets implicated in Mtb cell wall biosynthesis

Summary

Introduction

Mycobacterium tuberculosis (Mtb) is a pathogenic microorganism that targets alveolar macrophages and induces tuberculosis in humans and animals [1]. Tuberculosis is one of the main global health challenges of all time. The current antitubercular drugs applied in the clinic have lessened mortality, Mtb resistance to these medications has become a global challenge facing public health [2,3]. Galactofuranose (Galf ) is a critical part of the arabinogalactan that connects the peptidoglycan layer and the mycolic acid layer in the cell wall of Mtb [4]. Removal of the gene encoding for UGM in Mtb revealed that this enzyme is necessary for mycobacterial cell wall biosynthesis. Since Galf and UGM are not detected in humans, UGM has been reported to be a vital target for therapeutic intervention [6,7]

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