Macrolide, Lincosamide, Streptogramin, Ketolide, and Oxazolidinone Resistance

Marilyn C. Roberts; Joyce Sutcliffe

doi:10.1128/9781555817572.ch6

Chapter 6 : Macrolide, Lincosamide, Streptogramin, Ketolide, and Oxazolidinone Resistance

Authors: Marilyn C. Roberts¹, Joyce Sutcliffe³

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Affiliations: 1: Department of Pathobiology, Box 357238, University of Washington, Seattle, WA 98195; 2: Department of Pathobiology, Box 357238, University of Washington, Seattle, WA 98195; 3: Rib-X Pharmaceuticals, Inc., New Haven, CT 06511

Content Type: Monograph

Publication Year: 2005

Category: Bacterial Pathogenesis

Book DOI: 10.1128/9781555817572

Chapter DOI: 10.1128/9781555817572.ch6

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Abstract:

Macrolides, lincosamides, streptogramins, ketolides, and oxazolidinones (MLSKO), though chemically distinct, share overlapping binding sites on the 50S subunit of the ribosome. Bacteria acquire resistance to one or more of these antibiotics by the acquisition of a gene(s) or with certain mutations. The ketolides are macrolide derivatives that have recently become available for human therapy. The lincosamides are a distinct group of antibiotics that are structurally unrelated to macrolides. The streptogramin B component shares an overlapping ribosomal binding site, on the 50S ribosomal subunit, with the macrolides and lincosamides and is impacted by erm methylation at A2058 (Escherichia coli numbering). The MLSKO antibiotics inhibit protein synthesis by binding to the 50S ribosomal subunit and blocking peptide bond formation and/or translation. The binding of 14-, 15-, and 16-membered macrolides, clindamycin, and two ketolides has been described in this chapter. The Mycobacterium erm genes are regulated at the translation step. These genes confer resistance to macrolides and lincosamides but not to streptogramin B. Mutations associated with resistance to macrolides, ketolides, streptogramins, or oxazolidinones have been described in the chapter. However, with the addition of the newer macrolides, streptogramins, ketolides, and oxazolidinones, use of this group of antibiotics has increased, and today they are important in the treatment of a variety of infectious diseases in both community and hospital environments. Ketolide resistance in streptococci and oxazolidinone resistance in gram-positive enterococci or staphylococci are surfacing with increased therapeutic use.

Citation: Roberts M, Sutcliffe J. 2005. Macrolide, Lincosamide, Streptogramin, Ketolide, and Oxazolidinone Resistance, p 66-84. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch6

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Macrolide, Lincosamide, Streptogramin, Ketolide, and Oxazolidinone Resistance

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Figure 1a

Structures of the various MLSKO antibiotics. (Continued on following page.)

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Figure 1a

Structures of the various MLSKO antibiotics. (Continued on following page.)

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Figure 1b

Structures of the various MLSKO antibiotics. (Continued on following page.)

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Figure 1b

Structures of the various MLSKO antibiotics. (Continued on following page.)

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Tables

Macrolide, Lincosamide, Streptogramin, Ketolide, and Oxazolidinone Resistance

/content/10.1128/9781555817572.chap6.tab6-1

Table 1

Mechanism of resistance a

a http://faculty.washington.edu/marilynr.

b See reference 27.

c See reference 80a.

d See reference 46a.

10.1128/9781555817572/tab6-1_thmb.gif

10.1128/9781555817572/tab6-1.gif

Table 1

Mechanism of resistance a

a http://faculty.washington.edu/marilynr.

b See reference 27.

c See reference 80a.

d See reference 46a.

/content/10.1128/9781555817572.chap6.tab6-2

Table 2

Bacteria carrying specific resistance genes a

a The erm(B) gene is the only rRNA methylase screened for in enteric gram-negative bacteria. Thus the distribution of other erm genes in aerobic gram-negative genera is most likely underrepresented in the table.

b http://faculty.washington.edu/marilynr. This website is updated yearly.

c Macrolide-lincosamide-streptogramin B resistance.

d Resistance to either lincomycin, oleandomycin, spriamycin, tylosin, or streptogramin A or both erythromycin and streptogramin B.

e Reference 153, the msr(D) gene may not be functional.

f Resistance to either lincomycin or erythromycin.

g The mef(A) gene produces a truncated protein which is missing N-terminal amino acids and most likely is not functional.

h Resistance to erythromycin.

i Resistance to streptogramin B.

j Resistance to either lincomycin or streptogramin A.

k Resistance to macrolides.

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Table 2

Bacteria carrying specific resistance genes a

b http://faculty.washington.edu/marilynr. This website is updated yearly.

c Macrolide-lincosamide-streptogramin B resistance.

d Resistance to either lincomycin, oleandomycin, spriamycin, tylosin, or streptogramin A or both erythromycin and streptogramin B.

e Reference 153, the msr(D) gene may not be functional.

f Resistance to either lincomycin or erythromycin.

g The mef(A) gene produces a truncated protein which is missing N-terminal amino acids and most likely is not functional.

h Resistance to erythromycin.

i Resistance to streptogramin B.

j Resistance to either lincomycin or streptogramin A.

k Resistance to macrolides.

/content/10.1128/9781555817572.chap6.tab6-3

Table 3

Species identified with 23S rRNA, L4, and/or L22 ribosomal protein mutations conferring resistance to MLSKO antibiotics a

a Data from references 11 , 18a , 30 , 35 , 54 , 59a , 62 , 79 - 80 , 86 , 95 , 96 , 102a , 103 , 106 , 107a , 135 , 138 , 139 , 142 , and 163 .

b At either the A2058 or A2059 position with E. coli numbering

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Table 3

Species identified with 23S rRNA, L4, and/or L22 ribosomal protein mutations conferring resistance to MLSKO antibiotics a

a Data from references 11 , 18a , 30 , 35 , 54 , 59a , 62 , 79 - 80 , 86 , 95 , 96 , 102a , 103 , 106 , 107a , 135 , 138 , 139 , 142 , and 163 .

b At either the A2058 or A2059 position with E. coli numbering

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Table 4

MLSKO antibiotic resistance genes linked to other antibiotic resistance genes or elements a

a This table is meant to illustrate the diversity of the genes and elements that the MLS genes have been linked to ( 2 – 5 , 16 , 27 , 38 , 40 , 43 , 45 , 52 , 53 , 83 , 85 , 104 , 112 , 120 , 145 , 153 ).

b The mef(A) and the msr(D) genes appear to be together in all clinical isolates examined from any genera; however, when cloned separately into naive strains of S. pneumoniae, both conferred macrolide resistance alone ( 27 ).

c Integron codes for an integrase (IntI) that mediates recombination between a recombination site (attI) and a target recombination sequence (attC; 59-base element.).

d Required for high level erythromycin resistance in E. coli.

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Table 4

MLSKO antibiotic resistance genes linked to other antibiotic resistance genes or elements a

c Integron codes for an integrase (IntI) that mediates recombination between a recombination site (attI) and a target recombination sequence (attC; 59-base element.).

d Required for high level erythromycin resistance in E. coli.