Resistance to Macrolide Antibiotics in Public Health Pathogens

Abstract

Macrolide resistance mechanisms can be target-based with a change in a 23S ribosomal RNA (rRNA) residue or a mutation in ribosomal protein L4 or L22 affecting the ribosome's interaction with the antibiotic. Alternatively, mono- or dimethylation of A2058 in domain V of the 23S rRNA by an acquired rRNA methyltransferase, the product of an erm (erythromycin ribosome methylation) gene, can interfere with antibiotic binding. Acquired genes encoding efflux pumps, most predominantly mef(A) + msr(D) in pneumococci/streptococci and msr(A/B) in staphylococci, also mediate resistance. Drug-inactivating mechanisms include phosphorylation of the 2'-hydroxyl of the amino sugar found at position C5 by phosphotransferases and hydrolysis of the macrocyclic lactone by esterases. These acquired genes are regulated by either translation or transcription attenuation, largely because cells are less fit when these genes, especially the rRNA methyltransferases, are highly induced or constitutively expressed. The induction of gene expression is cleverly tied to the mechanism of action of macrolides, relying on antibiotic-bound ribosomes stalled at specific sequences of nascent polypeptides to promote transcription or translation of downstream sequences.

Figure 1.

Structures of 14- and 15-membered macrolides.

Figure 2.

Structures of 16-membered macrolides.

Figure 3.

A model based on the crystal structure of the 70S Escherichia coli ribosome bound to erythromycin (PDB ID codes 3OFO, 3OFP, 3OFR, 3OFQ), telithromycin (PDB ID codes 3OAQ, 3OAR, 3OAS, 3OAT), and solithromycin (PDB ID code 4WWW) (Dunkle et al. 2010; Llano-Sotelo et al. 2010). (A) A comparison of the conformations of erythromycin (ERY, magenta), telithromycin (TEL, gold), and solithromycin (SOL, green) in their binding sites at the top of the nascent peptide exit tunnel (PET) comprised of 23S ribosomal RNA (rRNA). 23S rRNA residues are marked, with nitrogen in dark blue and oxygen in red. Hydrogen bonds are indicated between residues by dotted lines, including between residues U2609 in domain V and A752 in domain II of 23S rRNA. The alkyl–aryl arm of telithromycin and solithromycin is shown stacking with A752. (B) Erythromycin-only view. The key hydrogen bond between the 2′ hydroxyl of the desosamine and the N1 of A2058 is indicated. The exocyclic N6 amino group that is methylated by Erm methyltransferases is notable next to the N1 of A2058. (C) Solithromycin-only view. The left side of the figure displays solithromycin in the same conformation as macrolides in A and B. The C2-F is visible through the ring of C2611, but a better view of its interaction with C2611 is displayed when the view is rotated by 90°, with the C2-F stacking with the hydrophobic side of C2611. C2611 is paired through three hydrogen bonds to G2057.

Figure 4.

The secondary structure of the 3′ region of 23S ribosomal RNA (rRNA) domain V. Nucleotides in red indicate mutations that can yield 14/15-membered macrolide, 16-membered macrolide, and/or ketolide resistance (see Schwarz et al. 2016 for mutations in this region that alter lincosamides, streptogramins, phenicols, and pleuromutilins). rRNA helices that stem from this region are designated with dotted lines. Residue A752 is in the hairpin 35 loop of domain II.