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Review
. 2016 Nov 1;6(11):a027037.
doi: 10.1101/cshperspect.a027037.

Lincosamides, Streptogramins, Phenicols, and Pleuromutilins: Mode of Action and Mechanisms of Resistance

Stefan Schwarz  1   2 , Jianzhong Shen  2 , Kristina Kadlec  1 , Yang Wang  2 , Geovana Brenner Michael  1 , Andrea T Feßler  1 , Birte Vester  3
Affiliations
Review

Lincosamides, Streptogramins, Phenicols, and Pleuromutilins: Mode of Action and Mechanisms of Resistance

Stefan Schwarz et al. Cold Spring Harb Perspect Med. .

Abstract

Lincosamides, streptogramins, phenicols, and pleuromutilins (LSPPs) represent four structurally different classes of antimicrobial agents that inhibit bacterial protein synthesis by binding to particular sites on the 50S ribosomal subunit of the ribosomes. Members of all four classes are used for different purposes in human and veterinary medicine in various countries worldwide. Bacteria have developed ways and means to escape the inhibitory effects of LSPP antimicrobial agents by enzymatic inactivation, active export, or modification of the target sites of the agents. This review provides a comprehensive overview of the mode of action of LSPP antimicrobial agents as well as of the mutations and resistance genes known to confer resistance to these agents in various bacteria of human and animal origin.

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Figures

Figure 1.
Figure 1.
Structural formulas of the lincosamides, streptogramins, phenicols, and pleuromutilins (LSPP) antimicrobial agents. (A) The lincosamides lincomycin, clindamycin, and pirlimycin, (B) the streptogramin A dalfopristin and the streptogramin B quinupristin, (C) the phenicols chloramphenicol, thiamphenicol, and florfenicol, and (D) the pleuromutilins tiamulin, valnemulin, and retapamulin.
Figure 2.
Figure 2.
Lincosamides, streptogramins, phenicols, and pleuromutilins (LSPP) binding to the ribosome. (A) A model of the Escherichia coli bacterial ribosome with the two ribosomal subunits (based on RCSB Protein Data Bank [PDB] 4V9D; see rcsb.org, last accessed August 9, 2015), 30S with RNA in light yellow and proteins in darker yellow, 50S with RNA in grey and proteins in greenish. The magenta is the anticodon tip of tRNA in P-site. (B) A cut-view of the 50S subunit from A with a streptogramin A molecule (dalfopristin from PDB 4U26) in red to mark the peptidyltransferase center (PTC) area. The square marks the approximate area shown as a blow-up in C. (C) The overlapping binding sites of lincosamides, streptogramins, phenicols, and pleuromutilins exemplified by clindamycin (in pink) from PDB 4V7T, quinupristin (in yellow), and dalfopristin (in red) from PDB 4U26, chloramphenicol (in green) from PDB 4V7V, and tiamulin (in blue) from PDB 1XBP, respectively, and all placed in the E. coli structure. All PDB structures are from rcsb.org/pdb/home/home.do (Berman et al. 2000). The colored nucleotide bases indicate the positions methylated by Erm and Cfr methyltransferases. Nucleotides “in front” of the antimicrobial agents have been removed to be able to see the agents in their binding site.
Figure 3.
Figure 3.
A secondary structure model of the peptidyl transferase loop of domain V of 23S rRNA (Escherichia coli sequence and numbering) with nucleotides providing antibiotic resistance marked with gray circles. Data are all from bacteria except the streptogramin A data that come from an archae (Porse and Garrett 1999). The bacterial data are from the following studies: Douthwaite (1992), Vester and Douthwaite (2001), Miller et al. (2008), Long et al. (2009, 2010), and Li et al. (2011), and references herein. The smaller circles indicate resistance to the various antibiotics and with the same color code as in Figure 2.
Figure 4.
Figure 4.
lsa(E)- and lnu(B)-carrying multiresistance gene clusters. Schematic presentation of the structural variability among lsa(E) and lnu(B)-carrying multiresistance gene clusters found on plasmids or in the chromosomal DNA of Enterococcus faecalis, E. faecium, Streptococcus agalactiae, Erysipelothrix rhusiopathiae, MRSA (methicillin-resistant Staphylococcus aureus), and MSSA (methicillin-susceptible S. aureus). All genes are indicated by arrows with the arrowhead showing the direction of transcription. Insertion sequences are presented as gray boxes with the arrow inside indicating the transposase gene. All antimicrobial resistance genes are depicted as violet arrows. aacA-aphD, gentamicin/kanamycin/tobramycin resistance; aadE, streptomycin resistance; aphA3, kanamycin/neomycin resistance; erm(B), MLSB resistance; lnu(B), lincosamide resistance; lsa(E), lincosamide/pleuromutilin/streptogramin A resistance; spw, spectinomycin resistance; sat4, streptothricin resistance. Genes involved in transposition are shown in yellow, whereas the genes involved in plasmid replication and plasmid recombination/mobilization are shown in green and blue, respectively. Genes with other functions are displayed in white. The Δ symbol indicates a truncated gene. A 1-kb scale is shown in the upper right corner. The gray-shaded regions show >99% sequence identity.
Figure 5.
Figure 5.
Schematic presentation of the structural variability in the regions surrounding the cfr gene on plasmids or in the chromosomal DNA of various Gram-positive and Gram-negative bacteria. All genes are indicated by arrows with the arrowhead showing the direction of transcription. Insertion sequences are presented as gray boxes with the arrow inside indicating the transposase gene. The cfr gene is shown as a red arrow, whereas all other antimicrobial resistance genes are depicted as violet arrows. Genes involved in transposition are shown in yellow, whereas the genes involved in plasmid replication and plasmid recombination/mobilization are shown in green and blue, respectively. Genes with other functions are displayed in white. The Δ symbol indicates a truncated gene. A 1-kb scale is shown in the upper left corner. aadD, kanamycin/neomycin resistance; aadY, streptomycin resistance; aacA-aphD, gentamicin/kanamycin/tobramycin resistance; ble, bleomycin resistance; dfrK, trimethoprim resistance, erm(A), erm(B), erm(C), erm(33), MLSB resistance; fexA, chloramphenicol/florfenicol resistance; lsa(B), elevated minimum inhibitory concentrations (MICs) of lincosamides; spc, spectinomycin resistance; tet(L), tetracycline resistance.
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