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) þ msr(D) in pneumococci/streptococci and msr(A/B) in staphylococci, also mediate resistance. Drug-inactivating mechanisms include phosphorylation of the 2 0 -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. Macrolide antibiotics are polyketides composed of a 14-, 15-, or 16-membered macrocyclic lactone ring (14-, 15-, and 16-membered) to which several sugars and/or side chains have been attached by the producing organism or as modifications during semisynthesis in the laboratory (Figs. 1 and 2). Newer semisynthetic derivations, like ketolides telithromycin, and solithromycin, have a C3-keto group in place of the C3 cladinose (akin to naturally occurring pikromycin) (Brockmann and Henkel 1950) and an 11,12-cyclic carbamate with an extended alkyl -aryl side chain that increases the affinity of the antibiotic for the ribosome by 10-to 100-fold (Hansen et al. 1999;Dunkle et al. 2010); in the case of solithromycin, a fluorine substituent at C2 provides an additional ribosomal interaction (Llano-Sotelo et al. 2010). Macrolides continue to be important in the therapeutic treatment of community-acquired pneumonia (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and atypicals Legionella pneumophila, Mycoplasma pneumoniae, Chlamydia pneumoniae), sexually transmitted diseases (Neiserria gonorhoeae, Chlamydia trachomatis, Mycoplasma genitalium), shigellosis, and salmonellosis. With solithromycin heading for a new drug application (NDA) filing in 2016 and having the in vitro potency to treat erythromycin-resistant

The macrolide antibiotic renaissance

“…coli (Nunez‐Samudio and Chesneau, ). Recently, additional mef genes were described, namely, mef (B) and mef (E), with medium homology to mef (A) and mef (I), as well as mef (O) with high homology to mef (A) (see Fyfe et al ., ). mef genes are regulated by transcription attenuation, with the induction of the mef (E)/ msr (D) operon occurring by anti‐attenuation of transcription in the presence of inducing macrolides.…”

“…aureus (Matsuoka et al ., , ), Enterococcus (Portillo et al ., ), Streptococcus (Varaldo et al ., ), Pseudomonas and Corynebacterium (Ojo et al ., ). For a long time, the Msr family was thought to confer macrolide resistance by acting as efflux pumps (Fyfe et al ., ). Now, it seems that these proteins act in a similar way to TetM/TetO proteins, chasing the bound macrolide from the ribosome (Sharkey et al ., ; Wilson, ).…”

“…pneumoniae (Vester and Douthwaite, ). Mutations at position 2057 have also been observed in clinical isolates although with a limited frequency (Fyfe et al ., ). The U2609C mutation in E .…”

“…The two most common resistance mechanisms in the bacterial pathogens are the reduced binding affinity of the drug, firstly, due to modification of either the bacterial ribosome or the antibiotic molecule and, secondly, due to efflux of macrolides from the bacterial cell, arising via altering either the membrane permeability or efflux pump expression (Wilson, 2014;Fyfe et al, 2016). Efflux proteins belong mainly to Mef and Msr families, and ribosome modification mechanisms include either ribosomal 23S rRNA or large ribosomal subunit proteins, while drug-inactivating mechanisms include phosphorylation of the 2 0 -hydroxyl of the sugar by phosphotransferases and hydrolysis of the macrocyclic lactone by esterases.…”

“…Msr (D) and Mef(E) co-expression is required for high-level macrolide resistance in S. pneumoniae, and both proteins interact synergistically to increase macrolide resistance in E. coli (Nunez-Samudio and Chesneau, 2013). Recently, additional mef genes were described, namely, mef(B) and mef (E), with medium homology to mef(A) and mef(I), as well as mef(O) with high homology to mef(A) (see Fyfe et al, 2016). mef genes are regulated by transcription attenuation, with the induction of the mef(E)/msr(D) operon occurring by anti-attenuation of transcription in the presence of inducing macrolides.…”