The natural antibiotic mucpirocin, which is used in the clinic, inhibits the isoleucyl-tRNA synthetase (IleRS) 1 but not the resistant IleRS2, which can individually occur in a given bacteria or co-exist. The Gruic-Sovulj Lab (University of Zagreb) and the Ban lab (ETH Zurich) investigated the structural basis for the resistance of IleRS2 and show how mutations in some IleRS2 variants laying within a signature motif of this class of tRNA-synthetases lead to hyper-resitance to mucipirocin, and could explain why these mutations were not possible to acquire in IleRS1. Their findings have been published in the article "Antibiotic hyper-resistance in a class I aminoacyl-tRNA synthetase with altered active site signature motif" in Nature Communications.
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 tRNAIle 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 class I aminoacyl-tRNA synthetases to which IleRSs belong. The structural analysis demonstrates how an altered HIGH motif could be adopted in IleRS2 but not IleRS1, providing insight into an elegant mechanism for coevolution of the key catalytic motif and associated antibiotic resistance.