Computational and biophysical validation of tobramycin targeting <i>Mycobacterium</i> MetE(Rv1133c): implications for anti-tuberculosis activity & rifampicin synergy

We hypothesize that this inhibition involves classical 30S ribosomal binding and MetE disruption. Most significantly, we discovered a powerful synergistic effect between tobramycin and the first-line anti-TB drug, rifampicin. Together, these findings establish a robust preclinical foundation for repurposing tobramycin against management of tuberculosis.</p> <p>Flowchart illustrating tuberculosis treatment strategies, including DOTS, drug repurposing, and virtual screening.The image is a flowchart summarizing tuberculosis (TB) treatment strategies.

At the top, "infected lungs" and an inset depicting active TB in alveolar macrophages highlight the infection. Below, treatment paths show "DOTS Treatment" with limits for multidrug-resistant (MDR) and extensively drug-resistant TB (XDR-TB) crossed out, while "Drug Repurposing" indicates potential benefits for these strains. Arrows lead to an "FDA approved drug library" connected to "Virtual Screening" that produces "Tobramycin" and progresses to "Biophysical Characterization of MetE-Tobramycin".

Results include "Synergy with Rifampicin" and "In-vitro anti-mycobacterial activity".</p> <p></p><p>For the first time we are establishing MetE as a drug target in <i>M.tb</i> which is absent in humans, making it crucial.</p><p>As a part of drug repurposing, for the first time we are validating tobramycin as the first-known inhibitor of MetE.</p><p>We propose that tobramycin’s anti-mycobacterial efficacy is driven by a combination of its classical role in inhibiting protein synthesis and disruption of MetE-mediated methionine biosynthesis.</p><p>We demonstrated synergistic interaction between tobramycin and rifampicin.

This combinatory therapy drastically reduces the required concentrations of both drugs, offering a novel anti-TB strategy with the potential to lower costs, shorten treatment, and combat MDR-TB.</p><p></p> <p>For the first time we are establishing MetE as a drug target in <i>M.tb</i> which is absent in humans, making it crucial.</p> <p>As a part of drug repurposing, for the first time we are validating tobramycin as the first-known inhibitor of MetE.</p> <p>We propose that tobramycin’s anti-mycobacterial efficacy is driven by a combination of its classical role in inhibiting protein synthesis and disruption of MetE-mediated methionine biosynthesis.</p> <p>We demonstrated synergistic interaction between tobramycin and rifampicin.

This combinatory therapy drastically reduces the required concentrations of both drugs, offering a novel anti-TB strategy with the potential to lower costs, shorten treatment, and combat MDR-TB.</p>