Synthesis and antibacterial evaluation of trisindolines against methicillin-resistant Staphylococcus aureus targeting cell membrane.

IF 9.2 1区生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

npj Biofilms and Microbiomes Pub Date : 2025-09-24 DOI:10.1038/s41522-025-00739-1

Arti Rathore, Irshad Ahmad Zargar, Jyoti Kumari, Biplab Sarkar, Rakshit Manhas, Shifa Firdous, Ramajayan Pandian, Debaraj Mukherjee, Avisek Mahapa

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Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant global health threat that requires novel antimicrobials to combat this WHO-designated priority pathogen. In this study, we designed, synthesized and evaluated a series of unexplored trisindoline derivatives against MRSA, including multidrug-resistant (MDR) clinical isolates. The Structure Activity Relationship (SAR) analysis of the trisindolines indicated the importance of strategic substitutions in the trisindoline core for their anti-staphylococcal efficacy. Biocompatibility studies revealed a high safety profile for the active compounds across various mammalian cell lines. Furthermore, the derivatives displayed rapid bactericidal action, anti-biofilm efficacy, intracellular MRSA killing and combinatorial effect with vancomycin. Mechanistic studies revealed that these compounds disrupt MRSA cell integrity by influencing several membrane-related pathways. Finally, in vivo assessments of a lead trisindoline in an MRSA-induced systemic infection model demonstrated a significant reduction of bacterial load. Therefore, these trisindoline molecules may offer a promising therapeutic model for combating MRSA infections.

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三吲哚啉对靶向细胞膜的耐甲氧西林金黄色葡萄球菌的合成及抑菌评价。

耐甲氧西林金黄色葡萄球菌（MRSA）对全球健康构成重大威胁，需要新的抗微生物药物来对抗这一世卫组织指定的重点病原体。在本研究中，我们设计、合成并评估了一系列未开发的抗MRSA的三吲哚啉衍生物，包括耐多药（MDR）临床分离株。三吲哚啉的构效关系（SAR）分析表明，三吲哚啉核心的战略性取代对其抗葡萄球菌效果至关重要。生物相容性研究表明，活性化合物在各种哺乳动物细胞系中具有很高的安全性。此外，衍生物具有快速杀菌作用、抗生物膜作用、细胞内MRSA杀伤作用和与万古霉素的联合作用。机制研究表明，这些化合物通过影响几种膜相关途径破坏MRSA细胞的完整性。最后，在mrsa诱导的全身感染模型中，三吲哚啉铅的体内评估显示细菌负荷显著减少。因此，这些三吲哚啉分子可能为对抗MRSA感染提供了一种有希望的治疗模式。

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来源期刊

npj Biofilms and Microbiomes Immunology and Microbiology-Microbiology

CiteScore

12.10

自引率

3.30%

发文量

审稿时长

9 weeks

期刊介绍： npj Biofilms and Microbiomes is a comprehensive platform that promotes research on biofilms and microbiomes across various scientific disciplines. The journal facilitates cross-disciplinary discussions to enhance our understanding of the biology, ecology, and communal functions of biofilms, populations, and communities. It also focuses on applications in the medical, environmental, and engineering domains. The scope of the journal encompasses all aspects of the field, ranging from cell-cell communication and single cell interactions to the microbiomes of humans, animals, plants, and natural and built environments. The journal also welcomes research on the virome, phageome, mycome, and fungome. It publishes both applied science and theoretical work. As an open access and interdisciplinary journal, its primary goal is to publish significant scientific advancements in microbial biofilms and microbiomes. The journal enables discussions that span multiple disciplines and contributes to our understanding of the social behavior of microbial biofilm populations and communities, and their impact on life, human health, and the environment.