Antibiotic hyper-resistance in a class I aminoacyl-tRNA synthetase with altered active site signature motif.

ABSTRACT: Antibiotics target key biological processes that include protein synthesis. Bacteria respond by developing resistance, which increases rapidly due to antibiotics overuse. Mupirocin, a clinically used natural antibiotic, inhibits isoleucyl-tRNA synthetase (IleRS), an enzyme that links isoleucine to its tRNA^Ile for protein synthesis. Two IleRSs, mupirocin-sensitive IleRS1 and resistant IleRS2, coexist in bacteria. The latter may also be found in resistant Staphylococcus aureus clinical isolates. Here, we describe the structural basis of mupirocin resistance and unravel a mechanism of hyper-resistance evolved by some IleRS2 proteins. We surprisingly find that an up to 10³-fold increase in resistance originates from alteration of the HIGH motif, a signature motif of the c

SUBMITTER: Brkic A 

PROVIDER: S-EPMC10485003 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature