8UVS

Crystal structure of the wild-type Thermus thermophilus 70S ribosome in complex with spectinomycin derivative 2694, mRNA, deacylated A- and E-site tRNAphe, and deacylated P-site tRNAmet at 2.75A resolution

これはPDB形式変換不可エントリーです。

8UVS の概要

• エントリーDOI: 10.2210/pdb8uvs/pdb
• 分子名称: 23S Ribosomal RNA, 50S ribosomal protein L14, 50S ribosomal protein L15, ... (61 entities in total)
• 機能のキーワード: spectinomycin; aminomethyl spectinomycin; antibiotic; 70s ribosome; x-ray structure; inhibition of translation; infectious diseases; antimicrobial drug discovery; semisynthetic chemistry; drug development, ribosome, ribosome-inhibitor complex, ribosome/inhibitor
• 由来する生物種: Escherichia coli; 詳細
• タンパク質・核酸の鎖数: 112
• 化学式量合計: 4572867.66

構造登録者

Killam, B.Y.,Phelps, G.A.,Lee, R.E.,Polikanov, Y.S. (登録日: 2023-11-03, 公開日: 2024-08-07, 最終更新日: 2025-03-19)

主引用文献

Phelps, G.A.,Cheramie, M.N.,Fernando, D.M.,Selchow, P.,Meyer, C.J.,Waidyarachchi, S.L.,Dharuman, S.,Liu, J.,Meuli, M.,Molin, M.D.,Killam, B.Y.,Murphy, P.A.,Reeve, S.M.,Wilt, L.A.,Anderson, S.M.,Yang, L.,Lee, R.B.,Temrikar, Z.H.,Lukka, P.B.,Meibohm, B.,Polikanov, Y.S.,Hobbie, S.N.,Bottger, E.C.,Sander, P.,Lee, R.E.
Development of 2nd generation aminomethyl spectinomycins that overcome native efflux in Mycobacterium abscessus.
Proc.Natl.Acad.Sci.USA, 121:e2314101120-e2314101120, 2024

PubMed Abstract: (), a nontuberculous mycobacterial (NTM) species, is an emerging pathogen with high intrinsic drug resistance. Current standard-of-care therapy results in poor outcomes, demonstrating the urgent need to develop effective antimycobacterial regimens. Through synthetic modification of spectinomycin (SPC), we have identified a distinct structural subclass of N-ethylene linked aminomethyl SPCs (eAmSPCs) that are up to 64-fold more potent against over the parent SPC. Mechanism of action and crystallography studies demonstrate that the eAmSPCs display a mode of ribosomal inhibition consistent with SPC. However, they exert their increased antimicrobial activity through enhanced accumulation, largely by circumventing efflux mechanisms. The N-ethylene linkage within this series plays a critical role in avoiding TetV-mediated efflux, as lead eAmSPC 2593 displays a mere fourfold susceptibility improvement against Δ in contrast to the 64-fold increase for SPC. Even a minor shortening of the linkage by a single carbon, akin to 1st generation AmSPC 1950, results in a substantial increase in MICs and a 16-fold rise in susceptibility against Δ. These shifts suggest that longer linkages might modify the kinetics of drug expulsion by TetV, ultimately shifting the equilibrium towards heightened intracellular concentrations and enhanced antimicrobial efficacy. Furthermore, lead eAmSPCs were also shown to synergize with various classes of anti- antibiotics and retain activity against clinical isolates and other mycobacterial strains. Encouraging pharmacokinetic profiles coupled with robust efficacy in murine infection models suggest that eAmSPCs hold the potential to be developed into treatments for and other NTM infections.

PubMed: 38165935
DOI: 10.1073/pnas.2314101120
主引用文献が同じPDBエントリー

実験手法

X-RAY DIFFRACTION (2.75 Å)