RT Journal Article
SR Electronic
T1 Tetracenomycin X sequesters peptidyl-tRNA during translation of QK motifs
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.08.09.503329
DO 10.1101/2022.08.09.503329
A1 Leroy, Elodie C.
A1 Perry, Thomas N.
A1 Renault, Thibaud T.
A1 Innis, C. Axel
YR 2023
UL http://biorxiv.org/content/early/2023/01/24/2022.08.09.503329.abstract
AB With antibiotic-resistant bacteria threatening our ability to treat common infections, new lead compounds with distinct target binding sites and limited cross-resistance are urgently needed. Natural products that inhibit the bacterial ribosome – a target for more than half of the antibiotics in use today – are a promising source of such leads and have the potential to be developed into potent drugs through structure-guided design. However, because the mechanisms of action of many of these compounds are not well understood, they are often poor candidates for a structure-based approach. Here, we use inverse toeprinting coupled to next-generation sequencing to show that the aromatic polyketide tetracenomycin X (TcmX) primarily inhibits the formation of a peptide bond between an incoming aminoacyl-tRNA and a terminal Gln-Lys (QK) motif in the nascent polypeptide. Using cryogenic electron microscopy, we reveal that translation inhibition at QK motifs occurs via an unusual mechanism involving sequestration of the 3’ adenosine of peptidyl-tRNALys in the drug-occupied nascent polypeptide exit tunnel of the ribosome. Our study provides mechanistic insights into the mode of action of TcmX on the bacterial ribosome and suggests a path forward for the development of novel antibiotics based on a common aromatic polyketide scaffold.Competing Interest StatementThe authors have declared no competing interest.