Deletion of RsmE 16S rRNA methyltransferase leads to low level increase in aminoglycoside resistance in Mycobacterium smegmatis

Abstract

AbstractOwing to its central role in cellular function, ribosome is one of the most common targets of antibiotics in bacteria. Mutations in rrs gene, ribosomal protein genes, methyltransfersases or drug influx/efflux are often found to overcome the drug response. Despite modulation of methylation pattern in the ribosome through mutations in the methyltransferases as one of key modulators of drug response, rsmG (gidB) is the only conserved methyltransferase associated with low-level drug resistance in large number of mycobacterial isolates. Here, we present the first evidence of association of methylation by mycobacterial RsmE, that methylates U1498 of 16S rRNA, with low levels of drug resistance. Deletion of the RsmE-homolog of Mycobacterium smegmatis leads to at least two-fold increase in the inhibitory concentration of aminoglycosides that bind in the decoding center proximal to U1498 in the 30S subunit. The change in inhibitory concentrations was highly specific and does not show any cross-resistance to drugs of other classes. Surprisingly, Rv2372c, the RsmE-homolog of Mycobacterium tuberculosis has the largest number of mutations among conserved ribosomal methyltransfersases, after gidB, highlighting the role of mutations in the RsmE methyltransferase as a key emerging mechanism of drug resistance in clinical strains of M. tuberculosis. Our work underlies the association of methylation by the RsmE-homolog with drug resistance and lays the groundwork to tackle this emerging mechanism of drug resistane in mycobacteria.