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Publication Abstract from PubMed

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.

Structure-Based Analysis of Semisynthetic Anti-TB Rufomycin Analogues.,Zhou B, Shetye G, Klein LL, Wolf NM, Lee H, McAlpine JB, Harris G, Chen SN, Suh JW, Cho SH, Franzblau SG, Abad-Zapatero C, Pauli GF J Nat Prod. 2025 Mar 24. doi: 10.1021/acs.jnatprod.4c01266. PMID:40126472^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.