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<p>Fluoroquinolone (FQ) resistance in <i>Salmonella enterica</i> serotype Typhi (<i>S.</i> Typhi) poses a major public health challenge, primarily driven by mutations in DNA gyrase (GyrA). This study focused on the D538N mutation in GyrA, consistently identified across sequenced <i>S.</i> Typhi isolates. Functional impact of protein sequence variation revealed that the D538N mutation has a deleterious impact on protein function, which highlights its potential biological significance in resistant <i>S.</i> Typhi. To identify potential inhibitors against mutated GyrA, a curated library of phenolic and flavonoid compounds was screened using a multi-step computational approach. Compounds violating Lipinski’s rule were filtered out, and a CatBoost-based machine learning model (85% accuracy, AUC 0.91) predicted 258 active compounds. Molecular docking at the mutated GyrA site identified 10 lead compounds with favorable binding affinities (−8.0 to −7.1&#xa0;kcal/mol). Toxicity screening via ProTox-3.0 and ADMETlab 3.0 revealed four non-toxic candidates, further validated by 200 ns molecular dynamics (MD) simulations. MD analysis confirmed the stability of silymarin, liquiritin, and ononin complexes, with minimal structural fluctuations. MM-GBSA analysis ranked silymarin the most favorable binding energy (− 31.33 ± 6.63&#xa0;kcal/mol), followed by liquiritin and ononin. In conclusion, this study provides computational evidence suggesting that the D538N mutation in CTD may represent a novel functional site in GyrA and that natural compounds could serve as promising candidates for the development of alternative therapeutic agents against drug-resistant <i>S</i>. Typhi. These findings lay the groundwork for future experimental work aimed at validating and optimizing natural inhibitors targeting C-terminal regions of bacterial DNA gyrase.</p>

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Screening of natural compounds potentially inhibiting the mutated C-terminal domain of GyrA in Salmonella Typhi using ML-based in silico approach

  • 期刊论文

  • 发表日期：

    2025年11月4日

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  • Tushar Joshi,
  • Tanvika Raj Sharma,
  • Avani Panickar,
  • Shalini Mathpal,
  • Romita Guchhait,
  • Sudha Ramaiah,
  • Anand Anbarasu

摘要

Fluoroquinolone (FQ) resistance in Salmonella enterica serotype Typhi (S. Typhi) poses a major public health challenge, primarily driven by mutations in DNA gyrase (GyrA). This study focused on the D538N mutation in GyrA, consistently identified across sequenced S. Typhi isolates. Functional impact of protein sequence variation revealed that the D538N mutation has a deleterious impact on protein function, which highlights its potential biological significance in resistant S. Typhi. To identify potential inhibitors against mutated GyrA, a curated library of phenolic and flavonoid compounds was screened using a multi-step computational approach. Compounds violating Lipinski’s rule were filtered out, and a CatBoost-based machine learning model (85% accuracy, AUC 0.91) predicted 258 active compounds. Molecular docking at the mutated GyrA site identified 10 lead compounds with favorable binding affinities (−8.0 to −7.1 kcal/mol). Toxicity screening via ProTox-3.0 and ADMETlab 3.0 revealed four non-toxic candidates, further validated by 200 ns molecular dynamics (MD) simulations. MD analysis confirmed the stability of silymarin, liquiritin, and ononin complexes, with minimal structural fluctuations. MM-GBSA analysis ranked silymarin the most favorable binding energy (− 31.33 ± 6.63 kcal/mol), followed by liquiritin and ononin. In conclusion, this study provides computational evidence suggesting that the D538N mutation in CTD may represent a novel functional site in GyrA and that natural compounds could serve as promising candidates for the development of alternative therapeutic agents against drug-resistant S. Typhi. These findings lay the groundwork for future experimental work aimed at validating and optimizing natural inhibitors targeting C-terminal regions of bacterial DNA gyrase.