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<p><i>Orientia tsutsugamushi (OT),</i> an obligate intracellular Gram-negative bacterium of the Rickettsiaceae family, causes scrub typhus (ST), a re-emerging vector-borne infectious disease with significant morbidity and mortality in South and Southeast Asia. Despite its widespread prevalence and mortality rates reaching up to 30% in untreated individuals, no effective vaccines or targeted therapeutics are currently available.Compounding these challenges are limitations in existing diagnostic methods, increasing antibiotic resistance, and complex interactions among host, pathogen, and vector. To address these critical gaps, this study conducted a comprehensive genome-wide comparative analysis across 23 OT strains, including UT 76, Karp, Kato, Gilliam, and Wuj/2014, using an in-house R-based computational pipeline. This analysis identified a conserved core genome of 744 genes, of which 19 are unique and pathogen- specific proteins. Subcellular localisation analyses revealed that nine of these proteins are membrane- associated, highlighting their potential accessibility to therapeutic agents. Additionally, proteins were prioritised through an integrative analysis that incorporates protein- protein interaction networks, druggability assessments, and antigenicity profiling. Six key proteins- dnaK, fusA, fabG, infB, nuoN and fabI were identified based on their essential roles in pathogen- specific pathways. These proteins are involved in membrane transport, transcription regulation, and biosynthesis, making them promising drug targets. Notably, this study employs in silico methodologies to overcome limitations inherent to traditional <i>wet-lab</i> approaches. Computational strategies are cost-effective for identifying conserved targets and supporting hypothesis- driven drug discovery. The findings presented here not only reveal previously uncharacterized therapeutic targets but also establish a genomic framework to improve diagnostic accuracy and guide future drug development against ST.</p>

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A proteome-driven strategy to discover novel therapeutic targets in Orientia tsutsugamushi

  • 期刊论文

  • 发表日期：

    2026年6月28日

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  • Koushik Paul,
  • Indu Kumari,
  • Sandeep Swargam

摘要

Orientia tsutsugamushi (OT), an obligate intracellular Gram-negative bacterium of the Rickettsiaceae family, causes scrub typhus (ST), a re-emerging vector-borne infectious disease with significant morbidity and mortality in South and Southeast Asia. Despite its widespread prevalence and mortality rates reaching up to 30% in untreated individuals, no effective vaccines or targeted therapeutics are currently available.Compounding these challenges are limitations in existing diagnostic methods, increasing antibiotic resistance, and complex interactions among host, pathogen, and vector. To address these critical gaps, this study conducted a comprehensive genome-wide comparative analysis across 23 OT strains, including UT 76, Karp, Kato, Gilliam, and Wuj/2014, using an in-house R-based computational pipeline. This analysis identified a conserved core genome of 744 genes, of which 19 are unique and pathogen- specific proteins. Subcellular localisation analyses revealed that nine of these proteins are membrane- associated, highlighting their potential accessibility to therapeutic agents. Additionally, proteins were prioritised through an integrative analysis that incorporates protein- protein interaction networks, druggability assessments, and antigenicity profiling. Six key proteins- dnaK, fusA, fabG, infB, nuoN and fabI were identified based on their essential roles in pathogen- specific pathways. These proteins are involved in membrane transport, transcription regulation, and biosynthesis, making them promising drug targets. Notably, this study employs in silico methodologies to overcome limitations inherent to traditional wet-lab approaches. Computational strategies are cost-effective for identifying conserved targets and supporting hypothesis- driven drug discovery. The findings presented here not only reveal previously uncharacterized therapeutic targets but also establish a genomic framework to improve diagnostic accuracy and guide future drug development against ST.