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bioRxiv · 10.1101/2024.03.02.583126

Unlocking Herbal Potentials: Novel Shikimate Kinase Inhibitors in the Fight Against Antibiotic Resistance

Nirgudkar, S.·Chai, Y.
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Abstract

Against a backdrop of stagnant antibiotic innovation, the escalating prevalence of antibiotic-resistant pathogens forecasts a challenging future [6]. Traditionally, antibiotics, predominantly derived from fungal sources, employ a limited set of mechanisms to inhibit bacterial growth [6, 16]. Shikimate Kinase has emerged as a promising antibacterial target due to its exclusivity to bacteria and the lethality of its inhibition [4, 13, 14, 15, 28, 29, 30]. Although synthetic inhibitors have been developed, the exploration of plant-derived alternatives remains untapped. Naturally derived plant-based compounds provide a more viable option because of the high cost of creating synthetic compounds. This study examines the Goldenrod plant, reputed in Native American Ethno-medicine for its antimicrobial properties [3, 12, 17]. Employing Liquid Chromatography - Mass Spectrometry (LC-MS) and Quantitative Structure Activity Relationship (QSAR) models, the study evaluates the plants compounds for their potential as antibacterial agents. Antibacterial activity against Bacillus Subtilis was assessed using the Kirby-Bauer Disk Diffusion assay, and genetic sequencing was performed on mutants that overcame the initial inhibition zone. By comparing the parent and mutant strains, the mode of inhibition by the plant antibiotic was determined by backtracking. The study identified Shikimate Kinase as the inhibitory target of the plant-derived compounds. Molecular docking revealed a binding affinity of -8.9 kcal/mol for the most effective compound, which is statistically significant compared to Shikimate Acid, the enzymes natural substrate. Through Pymol visualization, competitive inhibition was confirmed, with the compounds binding pocket exhibiting a druggability score of 0.84, approaching the threshold of clinical drugs. This research suggests new antibiotic classes targeting the Shikimate Kinase pathway, offering an alternative approach to tackling ESKAPE pathogens and enhancing health outcomes.

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Nirgudkar, S., Chai, Y.. 2024-03-03. Unlocking Herbal Potentials: Novel Shikimate Kinase Inhibitors in the Fight Against Antibiotic Resistance. https://doi.org/10.1101/2024.03.02.583126

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