RT Journal Article
SR Electronic
T1 Drug resistance through ribosome splitting and rRNA disordering in mycobacteria
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2024.06.13.598844
DO 10.1101/2024.06.13.598844
A1 Majumdar, Soneya
A1 Kashyap, Amuliya
A1 Koripella, Ravi K.
A1 Sharma, Manjuli R.
A1 Hurst-Hess, Kelley
A1 Manjari, Swati R.
A1 Banavali, Nilesh K.
A1 Ghosh, Pallavi
A1 Agrawal, Rajendra K.
YR 2024
UL http://biorxiv.org/content/early/2024/06/13/2024.06.13.598844.abstract
AB HflX is known to rescue stalled ribosomes and is implicated in antibiotic resistance in several bacteria. Here we present several high-resolution cryo-EM structures of mycobacterial HflX in complex with the ribosome and its 50S subunit, with and without antibiotics. These structures reveal a distinct mechanism for HflX- mediated ribosome splitting and antibiotic resistance in mycobacteria. In addition to dissociating ribosome into two subunits, mycobacterial HflX mediates persistent disordering of multiple 23S rRNA helices to generate an inactive pool of 50S subunits. Mycobacterial HflX also acts as an anti-association factor by binding to pre-dissociated 50S subunits. A mycobacteria-specific insertion in HflX reaches further into the peptidyl transferase center. The position of this insertion overlaps with ribosome-bound macrolides or lincosamide class of antibiotics. The extended conformation of insertion seen in the absence of these antibiotics retracts and adjusts around the bound antibiotics instead of physically displacing them. It therefore likely imparts antibiotic resistance by sequestration of the antibiotic- bound inactive 50S subunits.Competing Interest StatementThe authors have declared no competing interest.