Aminoglycoside Resistance: Updates with a Focus on Acquired 16S Ribosomal RNA Methyltransferases

Abstract

The clinical usefulness of aminoglycosides has been revisited as an effective choice against β-lactam-resistant and fluoroquinolone-resistant gram-negative bacterial infections. Plazomicin, a next-generation aminoglycoside, was introduced for the treatment of complicated urinary tract infections and acute pyelonephritis. In contrast, bacteria have resisted aminoglycosides, including plazomicin, by producing 16S ribosomal RNA (rRNA) methyltransferases (MTases) that confer high-level and broad-range aminoglycoside resistance. Aminoglycoside-resistant 16S rRNA MTase-producing gram-negative pathogens are widespread in various settings and are becoming a grave concern. This article provides up-to-date information with a focus on aminoglycoside-resistant 16S rRNA MTases.

Keywords: 16S rRNA methyltransferases; Aminoglycosides; Gram-negative bacteria; Plazomicin.

Fig. 1.

Core elements of aminoglycosides and aminoglycoside structures.

Fig. 2.

Mechanisms of methylation of G1405 and A1408 residues in 16S rRNA by aminoglycoside resistance 16S rRNA MTases.

Fig. 3.

(A) Three-dimensional structures of ArmA (gray), RmtB (orange), and RmtC (light green). These figures were rendered with Protein Data Bank (PDB) data (PDB identifier [ID], 3FZG, 3FRH, and 6PQB). The percentages indicate amino acid identities. (B) Binding mode between 16S rRNA (orange) and NpmA (green). The S-adenosyl-l-homocysteine (SAH) molecule is shown in yellow sticks and the A1408 residue in orange sticks. The 2 tryptophan residues (W107 and W197) of NpmA are shown in green sticks. This figure was rendered with PDB data (PDB ID, 4OX9).

Fig. 4.

Molecular models of binding mode between neomycin B/kanamycin A and wild G1405/m⁷G1405 in 16S rRNA. These figures were rendered based on crystal structures (PDB ID, 2ESI and 2ET4). Basic residues and aminoglycoside molecules are depicted in silver and green sticks, respectively, and the orange dashed lines indicate hydrogen bonds. The red translucent circle indicates the predicted position of the steric clash between the residue and aminoglycoside. MIC values were cited from references. (From Wachino J, Yamane K, Shibayama K, et al. Novel plasmid-mediated 16S rRNA methylase, RmtC, found in a Proteus mirabilis isolate demonstrating extraordinary high-level resistance against various aminoglycosides. Antimicrob Agents Chemother 2006;50(1):178–84 https://doi.org/10.1128/AAC.50.1.178-184.2006; with permission.)

Fig. 5.

Molecular models of binding mode between neomycin B/paromomycin/gentamicin C1a and wild A1408/m¹A1408 in 16S rRNA. The figures were rendered based on crystal structures (PDB ID, 2ET4, 5ZEM, 5ZEJ, and 2ET3). Basic residues and aminoglycoside molecules are depicted in orange and green sticks, respectively, and orange dashed lines indicate hydrogen bonds. The red translucent circle indicates the predicted position of the steric clash between the residue and aminoglycoside. MIC values were cited from references. (From Wachino J, Shibayama K, Kurokawa H, et al. Novel plasmid-mediated 16S rRNA m1A1408 methyltransferase, NpmA, found in a clinically isolated Escherichia coli strain resistant to structurally diverse aminoglycosides. Antimicrob Agents Chemother 2007;51(12):4401–9; with permission.)

Fig. 6.

Structure of plazomicin and modification targets of AMEs.