Computational evaluation of phytocompounds for combating drug resistant tuberculosis by multi-targeted therapy

Area of Science:

• Microbiology
• Biochemistry
• Drug Discovery

Background:

• Tuberculosis pathogenesis involves Mycobacterium tuberculosis cell wall interactions.
• L-rhamnose (L-Rha) links key cell wall components, and its synthesis pathway is absent in humans.
• Drug resistance and adverse effects necessitate new anti-TB therapies.

Purpose of the Study:

• To identify novel therapeutic agents targeting the L-rhamnose biosynthesis pathway.
• To explore phytocompounds as potential inhibitors of mycobacterial L-Rha synthesis.

Main Methods:

• Structure-based virtual screening of secondary metabolites against rhamnose pathway enzymes.
• Physicochemical and pharmacokinetic evaluations of potential drug leads.
• High-throughput screening and Microplate alamar blue assay (MABA) for anti-mycobacterial activity validation.

Main Results:

• Four phytocompounds (butein, diospyrin, indicanine, rumexneposide A) showed significant binding affinity to rhamnose pathway proteins.
• Butein, a secondary metabolite from Butea monosperma, demonstrated strong anti-tubercular activity.
• Butein's efficacy was confirmed via MABA, indicating promising anti-mycobacterial potential.

Conclusions:

• Inhibiting the L-rhamnose biosynthesis pathway is a viable strategy against Mycobacterium tuberculosis.
• Phytocompounds, particularly butein, represent promising novel agents for combating tuberculosis.
• Targeting specific pathways with novel agents can mitigate the development of bacterial resistance.