article · Scientific Reports
Drug-resistant strains of Mycobacterium tuberculosis present an urgent challenge to global disease control, driving the search for new therapeutics from natural sources. This research evaluated the antimycobacterial activity of crude extracts from bacteria isolated from South African gold mine tailings. Strains identified as Bacillus subtilis and Bacillus licheniformis demonstrated inhibitory activity against Mycobacterium tuberculosis H37Rv, Mycobacterium smegmatis, and Mycobacterium aurum. Chemical profiling identified bioactive natural constituents, which were screened computationally against two critical mycobacterial protein targets, Pks13 and PknG. Two compounds, cyclo-(L-Pro-4-OH-L-Leu) and vazabitide A, showed strong binding affinities for these targets. Subsequent computational modification of vazabitide A substantially enhanced its binding affinity to the Pks13 target site, demonstrating that extremophilic bacteria from mining environments offer viable molecular scaffolds for developing targeted anti-tuberculosis treatments.
Tuberculosis remains difficult to control because the causative bacteria frequently evolve resistance to conventional antibiotics. Discovering unique natural compounds from extreme environments, such as mine tailings, provides novel chemical structures that can inhibit essential bacterial proteins. This computational and laboratory screening establishes a starting point for designing improved drug candidates capable of overcoming existing drug resistance mechanisms.
This work is at an early discovery stage, relying on laboratory crude extract screening and computational molecular design. The identified compounds and modified variants could serve as lead scaffolds for pharmaceutical companies or medicinal chemistry researchers developing novel anti-tuberculosis drugs. Significant further work, including chemical synthesis and in vitro validation of the modified molecules, is required before any preclinical or commercial drug development pipeline can be established.
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Mycobacterial pathogens present a significant challenge to disease control efforts globally due to their inherent resistance to multiple antibiotics. The rise of drug-resistant strains of Mycobacterium tuberculosis has prompted an urgent need for innovative therapeutic solutions. One promising way to discover new tuberculosis drugs is by utilizing natural products from the vast biochemical space. Multidisciplinary methods can used to harness the bioactivity of these natural products. This study aimed to evaluate the antimycobacterial efficacy of functional crude extracts from bacteria isolated from gold mine tailings in South Africa. Bacterial strains were identified using 16S rRNA sequencing. The crude extracts obtained from the bacteria were tested against Mycobacterium tuberculosis H37Rv, Mycobacterium smegmatis mc<sup>2</sup>155, and Mycobacterium aurum A+. Untargeted HPLC-qTOF and molecular networking were used to identify the functional constituents present in extracts that exhibited inhibitory activity. A virtual screening workflow (VSW) was used to filter compounds that were strong binders to Mycobacterium tuberculosis Pks13 and PknG. The ligands returned from the VSW were subjected to optimization using density functional theory (DFT) at M06-2X/6-311++ (d,p) level of theory and basis set implemented in Gaussian16 Rev.C01. The optimized ligands were re-docked against Mycobacterium tuberculosis Pks13 and PknG. Molecular dynamics simulation and molecular mechanics generalized born surface area were used to evaluate the stability of the protein-ligand complexes formed by the identified hits. The hit that showed promising binding characteristics was virtually modified through multiple synthetic routes using reaction-driven enumeration. Three bacterial isolates showed significant activity against the two strains of Mycobacterium, while only two, Bacillus subtilis and Bacillus licheniformis, exhibited activity against both Mycobacterium tuberculosis H37Rv, Mycobacterium smegmatis mc<sup>2</sup>155, and Mycobacterium aurum A+. The tentatively identified compounds from the bacterial crude extracts belonged to various classes of natural compounds associated with antimicrobial activity. Two compounds, cyclo-(L-Pro-4-OH-L-Leu) and vazabitide A, showed strong binding against PknG and Pks13, with pre-MD MM-GBSA values of - 42.8 kcal/mol and - 47.6 kcal/mol, respectively. The DFT-optimized compounds exhibited the same docking scores as the ligands optimized using the OPSL-4 force field. After modifying vazabitide A, its affinity to the Pks13 binding site increased to - 85.8 kcal/mol, as revealed by the post-MD MM-GBSA analysis. This study highlights the potential of bacteria isolates from gold mine tailings as a source of new scaffolds for designing and optimizing anti-Mycobacterium agents. These agents synthesized in-silico can be further tested in-vitro to evaluate their efficacy.
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DOI: 10.1038/s41598-024-57124-9
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