Structural highlights
FunctionRPOA_ECOLI DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. This subunit plays an important role in subunit assembly since its dimerization is the first step in the sequential assembly of subunits to form the holoenzyme.[HAMAP-Rule:MF_00059] Publication Abstract from PubMedPseudouridimycin (PUM) is a C-nucleoside/peptide antibiotic that selectively inhibits bacterial RNA polymerase (RNAP) and exhibits potent activity against drug-resistant pathogens. However, PUM suffers from chemical instability due to self-immolative cleavage of its central hydroxamate bond. Here, we employed cryo-electron microscopy to determine structures of PUM (1) and a chemically stabilized des-hydroxy analog of PUM (2a) bound to an Escherichia coli RNAP transcription complex. Guided by the observed bound conformation, we developed an efficient solid-phase synthesis of 50 des-hydroxy PUM analogs modified at the Gln residue and Gdn-Gly tail. Several analogs retained low-micromolar RNAP-inhibitory activity, with a para-substituted phenyl amidine analog (54) emerging as the most potent inhibitor (IC(50) = 0.95 muM). These results establish a versatile synthetic platform and structural framework for optimizing stabilized PUM derivatives and provide a foundation for the development of RNAP-targeted therapeutics against resistant bacterial pathogens. Solid-phase synthesis and biological evaluation of des-hydroxy pseudouridimycin analogs.,Anwar AF, You L, Degen D, Burns KJ, Garza MJ, Ebright RH, Del Valle JR ACS Med Chem Lett. 2026 Mar 11:10.1021/acsmedchemlett.5c00684. doi: , 10.1021/acsmedchemlett.5c00684. PMID:41890570[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
This page was last modified 06:36, 8 April 2026.