Rahman Sudais, Liu Hsien, Shah Mohibuallah, Almutairi Mashal M, Liaqat Iram, Tanaka Tetsuya, Chen Chien-Chin, Alouffi Abdulaziz, Ali Abid
Department of Zoology, Abdul Wali Khan University, Mardan, Khyber Pakhtunkhwa, Pakistan.
Division of General Surgery, Department of Surgery, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan.
Front Vet Sci. 2025 Jan 16;11:1507496. doi: 10.3389/fvets.2024.1507496. eCollection 2024.
, responsible for flea-borne spotted fever, is a rising zoonotic pathogen posing an increasing global threat due to its expanding geographical distribution. The rise in antibiotic-resistant strains of this pathogen underscores the urgent need for new therapeutic interventions. This study employed a comprehensive subtractive proteomics analysis of the proteome, aiming to identify essential, non-host homologous, and pathogen-specific proteins, which were subsequently evaluated as potential new drug targets. These findings offer valuable insights into the development of therapeutic strategies against rickettsiosis. The analysis revealed 343 proteins that are non-homologous to the host, including 108 essential proteins, 25 unique metabolic pathways, and 11 distinct proteins. Out of these, 10 proteins were druggable in which two associated with virulence, and one related to resistance (succinate dehydrogenase). Through a rigorous screening process and extensive literature review, succinate dehydrogenase emerged as a promising drug target. Protein interaction partners for succinate dehydrogenase were identified using the STRING database. To further assess the functionality of succinate dehydrogenase, structure-based studies were conducted. Approximately 18,000 ZINC compounds were screened, leading to the finding of six potential inhibitors: ZINC67847806, ZINC67982856, ZINC67974679, ZINC67895371, ZINC05668040, and ZINC05670149. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling confirmed that most compounds met the preferred pharmacokinetic properties, except for ZINC67895371 and ZINC67847806, which exhibited positive ames test results, and ZINC05670149, ZINC67895371, and ZINC67847806, showed hepatotoxicity. All compounds were found to be non-sensitizing to the skin. Based on these findings, further experimental validation of ZINC67974679, ZINC67982856, and ZINC05668040 is recommended.
负责传播蚤传斑点热，是一种正在兴起的人畜共患病原体，由于其地理分布不断扩大，对全球构成越来越大的威胁。该病原体抗生素耐药菌株的增加凸显了对新治疗干预措施的迫切需求。本研究对该病原体的蛋白质组进行了全面的消减蛋白质组学分析，旨在鉴定必需的、非宿主同源的和病原体特异性的蛋白质，随后将这些蛋白质评估为潜在的新药物靶点。这些发现为立克次体病治疗策略的制定提供了有价值的见解。分析揭示了343种与宿主非同源的蛋白质，包括108种必需蛋白质、25条独特的代谢途径和11种不同的蛋白质。其中，10种蛋白质是可成药的，其中两种与毒力相关，一种与耐药性相关（琥珀酸脱氢酶）。通过严格的筛选过程和广泛的文献综述，琥珀酸脱氢酶成为一个有前景的药物靶点。使用STRING数据库鉴定了琥珀酸脱氢酶的蛋白质相互作用伙伴。为了进一步评估琥珀酸脱氢酶的功能，进行了基于结构的研究。筛选了大约18000种ZINC化合物，发现了六种潜在抑制剂：ZINC67847806、ZINC67982856、ZINC67974679、ZINC67895371、ZINC05668040和ZINC05670149。吸收、分布、代谢、排泄和毒性（ADMET）分析证实，除ZINC67895371和ZINC67847806表现出阳性艾姆斯试验结果，以及ZINC05670149、ZINC67895371和ZINC67847806表现出肝毒性外，大多数化合物符合优选的药代动力学性质。所有化合物均被发现对皮肤无致敏性。基于这些发现，建议对ZINC67974679、ZINC67982856和ZINC05668040进行进一步的实验验证。
