WeChat Mini Program
Old Version Features

Structure-Based Analysis of Semisynthetic Anti-TB Rufomycin Analogues.

Journal of natural products(2025)

Cited 0|Views3
Abstract
This study employed structural information from cocrystals of rufomycin 4 (1a) and caseinolytic protein C1 (ClpC1)-NTD-wt to guide design and semisynthesis of rufomycin analogues, evaluate their antituberculosis (TB) biological profiles, and establish structure-activity relationships (SAR). Covering three regions of interest (ROIs, A-C) as modification sites, 14 of the 30 semisynthetic analogues (2-31) showed similar or improved MICs relative to the main natural precursors, rufomycins 4/6 (1a/b). Compounds 5 and 27 exhibited up to 10-fold enhanced potency against Mycobacterium tuberculosis (Mtb) in vitro, with MIC values of 1.9 and 1.4 nM, respectively. Evaluation of ClpC1-binding properties used existing ClpC1-NTD complexes with rufomycin 4 (PDB: 6cn8) and ecumicin (PDB: 6pbs) as references. The newly reported X-ray ClpC1-NTD cocrystal structure of 11 (syn. But4-Cl) revealed significant conformational effects involving the side chains of certain amino acids of the heptapeptide and confirmed the importance of ROIs A-C for medicinal chemistry efforts. Observed interactions of the N-terminal tail of ClpC1 with the rufomycin analogues vs ecumicin explains their different modes of inactivating the ClpC1/P1/P2 homeostatic machinery. Collectively, the observations inform further SAR optimization strategies for the rufomycin class of antibiotics and complement our understanding of their mode of action.
More
Translated text
求助PDF
上传PDF
Bibtex
AI Read Science
AI Summary
AI Summary is the key point extracted automatically understanding the full text of the paper, including the background, methods, results, conclusions, icons and other key content, so that you can get the outline of the paper at a glance.
Example
Background
Key content
Introduction
Methods
Results
Related work
Fund
Key content
  • Pretraining has recently greatly promoted the development of natural language processing (NLP)
  • We show that M6 outperforms the baselines in multimodal downstream tasks, and the large M6 with 10 parameters can reach a better performance
  • We propose a method called M6 that is able to process information of multiple modalities and perform both single-modal and cross-modal understanding and generation
  • The model is scaled to large model with 10 billion parameters with sophisticated deployment, and the 10 -parameter M6-large is the largest pretrained model in Chinese
  • Experimental results show that our proposed M6 outperforms the baseline in a number of downstream tasks concerning both single modality and multiple modalities We will continue the pretraining of extremely large models by increasing data to explore the limit of its performance
Upload PDF to Generate Summary
Must-Reading Tree
Example
Generate MRT to find the research sequence of this paper
Data Disclaimer
The page data are from open Internet sources, cooperative publishers and automatic analysis results through AI technology. We do not make any commitments and guarantees for the validity, accuracy, correctness, reliability, completeness and timeliness of the page data. If you have any questions, please contact us by email: report@aminer.cn
Chat Paper
Summary is being generated by the instructions you defined