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
Structural highlights
FunctionRL6_THET8 This protein binds to the 23S rRNA, and is important in its secondary structure. It is located near the subunit interface in the base of the L7/L12 stalk, and near the tRNA binding site of the peptidyltransferase center.[HAMAP-Rule:MF_01365] Publication Abstract from PubMedMycobacterium abscessus (Mab), 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 Mab 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 Mab DeltatetV, 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 Mab DeltatetV. 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-Mab antibiotics and retain activity against clinical isolates and other mycobacterial strains. Encouraging pharmacokinetic profiles coupled with robust efficacy in Mab murine infection models suggest that eAmSPCs hold the potential to be developed into treatments for Mab and other NTM infections. Development of 2nd generation aminomethyl spectinomycins that overcome native efflux in Mycobacterium abscessus.,Phelps GA, Cheramie MN, Fernando DM, Selchow P, Meyer CJ, Waidyarachchi SL, Dharuman S, Liu J, Meuli M, Molin MD, Killam BY, Murphy PA, Reeve SM, Wilt LA, Anderson SM, Yang L, Lee RB, Temrikar ZH, Lukka PB, Meibohm B, Polikanov YS, Hobbie SN, Bottger EC, Sander P, Lee RE Proc Natl Acad Sci U S A. 2024 Jan 9;121(2):e2314101120. doi: , 10.1073/pnas.2314101120. Epub 2024 Jan 2. PMID:38165935[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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