Resistance to Macrolide Antibiotics in Public Health Pathogenspe .Resistance to Macrolide...

download Resistance to Macrolide Antibiotics in Public Health Pathogenspe .Resistance to Macrolide Antibiotics

of 38

  • date post

    23-Jul-2019
  • Category

    Documents

  • view

    213
  • download

    0

Embed Size (px)

Transcript of Resistance to Macrolide Antibiotics in Public Health Pathogenspe .Resistance to Macrolide...

  • Resistance to Macrolide Antibiotics in PublicHealth Pathogens

    Corey Fyfe, Trudy H. Grossman, Kathy Kerstein, and Joyce Sutcliffe

    Tetraphase Pharmaceuticals, Watertown, Massachusetts 02472

    Correspondence: jsutcliffe@tphase.com

    Macrolide resistance mechanisms can be target-based with a change in a 23S ribosomalRNA (rRNA) residue or a mutation in ribosomal protein L4 or L22 affecting the ribosomesinteraction with the antibiotic. Alternatively, mono- or dimethylation of A2058 in domainV of the 23S rRNA by an acquired rRNA methyltransferase, the product of an erm (erythro-mycin ribosome methylation) gene, can interfere with antibiotic binding. Acquired genesencoding efflux pumps, most predominantly mef(A) msr(D) in pneumococci/streptococciand msr(A/B) in staphylococci, also mediate resistance. Drug-inactivating mechanismsinclude phosphorylation of the 20-hydroxyl of the amino sugar found at position C5 byphosphotransferases and hydrolysis of the macrocyclic lactone by esterases. These acquiredgenes are regulated by either translation or transcription attenuation, largely because cellsare less fit when these genes, especially the rRNA methyltransferases, are highly induced orconstitutively expressed. The induction of gene expression is cleverly tied to the mechanismof action of macrolides, relying on antibiotic-bound ribosomes stalled at specific sequencesof nascent polypeptides to promote transcription or translation of downstream sequences.

    Macrolide antibiotics are polyketides com-posed of a 14-, 15-, or 16-membered mac-rocyclic lactone ring (14-, 15-, and 16-mem-bered) to which several sugars and/or sidechains have been attached by the producingorganism or as modifications during semisyn-thesis in the laboratory (Figs. 1 and 2). Newersemisynthetic derivations, like ketolides teli-thromycin, and solithromycin, have a C3-ketogroup in place of the C3 cladinose (akin to nat-urally occurring pikromycin) (Brockmann andHenkel 1950) and an 11,12-cyclic carbamatewith an extended alkylaryl side chain that in-creases the affinity of the antibiotic for the ri-bosome 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 addi-tional ribosomal interaction (Llano-Sotelo et al.2010). Macrolides continue to be important inthe therapeutic treatment of community-ac-quired pneumonia (Streptococcus pneumoniae,Haemophilus influenzae, Moraxella catarrhalis,and atypicals Legionella pneumophila, Myco-plasma pneumoniae, Chlamydia pneumoniae),sexually transmitted diseases (Neiserria gonor-hoeae, Chlamydia trachomatis, Mycoplasma gen-italium), shigellosis, and salmonellosis. Withsolithromycin heading for a new drug applica-tion (NDA) filing in 2016 and having the invitro potency to treat erythromycin-resistant

    Editors: Lynn L. Silver and Karen Bush

    Additional Perspectives on Antibiotics and Antibiotic Resistance available at www.perspectivesinmedicine.org

    Copyright # 2016 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a025395Cite this article as Cold Spring Harb Perspect Med 2016;6:a025395

    1

    ww

    w.p

    ersp

    ecti

    vesi

    nm

    edic

    ine.

    org

    on July 23, 2019 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from

    mailto:jsutcliffe@tphase.commailto:jsutcliffe@tphase.comhttp://www.perspectivesinmedicine.orghttp://www.perspectivesinmedicine.orghttp://www.perspectivesinmedicine.orghttp://perspectivesinmedicine.cshlp.org/
  • pneumococci and gonococci (Farrell et al.2015; Hook et al. 2015), macrolides/ketolideswill continue as an important part of the anti-biotic armamentarium.

    The mechanism of action of macrolides hasbeen further refined through a combination ofgenetic, biochemical, crystallographic, and ri-bosome profiling studies (Tu et al. 2005; Dunkleet al. 2010; Kannan et al. 2012, 2014; Gupta etal. 2016). Macrolides/ketolides are sensed bythe ribosome and, in the presence of certainmacrolide-stalling nascent amino acid chain-dependent motifs, selectively inhibit proteinsynthesis. Further, and to different extents, ke-tolides and macrolides cause frameshifting,leading to aberrant protein synthesis.

    Shortly after its clinical debut in 1953, resis-tance to erythromycin in staphylococci was de-scribed and was likely mediated by methylationof the 23S ribosomal RNA (rRNA) at nucleotideA2058 (Escherichia coli numbering) encodedby an erythromycin ribosomal methyltransfer-ase (erm) gene (Weisblum 1995a). Erm methyl-transferases add one or two methyl groupsto the N-6 exocyclic amino group of A2058,disrupting the key hydrogen bond betweenA2058 and the desosamine sugar at C5 (Fig.3). Ribosomal methylation by methyltransfer-ases encoded by erm genes remains the mostwidespread macrolide resistance in pathogenicbacteria, with certain erm genes more predom-inantly found in some species. Streptococci

    CH3 CH3

    CH3

    N(CH3)2CH3

    CH3

    CH3

    H3C

    HO R3

    OCH3

    CH3

    R1

    9

    R2

    C2H5

    O

    O

    O

    O OOH

    OH

    1

    4

    OCH3

    OH

    O

    R1 R2 R3

    Erythromycin

    Clarithromycin

    Roxithromycin

    O

    NOCH2OC2H4OCH3

    O OH

    OH

    OCH3O

    R1R

    F

    H

    Solithromycin

    Telithromycin

    NH2NNN

    NN

    N

    CH3 CH3

    H3C R2

    CH3

    N(CH3)2CH3OH

    CH3

    H3C

    H3C

    HO

    OCH3

    H3C

    R1N

    C2H5

    O

    OH

    O

    O OHO

    4O

    O OH

    R1

    CH3

    N(CH3)2CH3

    H3C

    CH3OCH3

    H3C

    H3C

    ON

    O

    H3C

    O

    R

    C2H5O

    O

    O

    O OHO

    1

    Oleandomycin H

    COCH3Troleandomycin

    R1, R2, R3

    Azithromycin

    Tulathromycin CH2NH(CH2)2CH3

    CH3

    H

    H

    R2R1

    CH3 OCH3OR3CH3

    CH3

    CH3N(CH3)2

    O

    O

    H3C

    H3C

    H3CC2H5

    O

    OR1

    O

    O OR2O

    O

    O

    Figure 1. Structures of 14- and 15-membered macrolides.

    C. Fyfe et al.

    2 Cite this article as Cold Spring Harb Perspect Med 2016;6:a025395

    ww

    w.p

    ersp

    ecti

    vesi

    nm

    edic

    ine.

    org

    on July 23, 2019 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from

    http://perspectivesinmedicine.cshlp.org/
  • generally have erm(B) or erm(A), subclasserm(TR), whereas erm(A), erm(B), or erm(C)are found in staphylococci and erm(F) in an-aerobes and H. influenzae (Table 2, and refer-ences therein; see also faculty.washington.edu/marilynr). There can be either mono- or di-methylation of A2058 and the degree of rRNAdimethylation can determine ketolide resistance(Douthwaite et al. 2005). Most erm genes areinducible by 14- and 15-membered macrolides,whereby translation repression of the erm meth-yltransferase gene, because of the sequestrationof its ribosome-binding site (RBS) by messen-ger RNA (mRNA) secondary structure, is re-lieved by binding of the inducer to the ribosome(Horinouchi and Weisblum 1980; Depardieuet al. 2007; Subramaniam et al. 2011). Upstreamof the start codon of a methyltransferase gene isan open reading frame (ORF) that producesleader peptides of different lengths (838 ami-no acids), each containing a macrolide stalling

    motif; when the macrolide-bound ribosomepauses, the attenuator, a stem and loop struc-ture that encompasses the RBS, is disrupted,resulting in ribosomal binding and synthesisof the methyltransferase (Subramaniam et al.2011; Arenz et al. 2014a,b). Although mosterm genes are regulated by translation attenua-tion, a few genes (e.g., erm(K)) are regulated bytranscription attenuation (Kwak et al. 1991;Choi et al. 1997) or through inducible tran-scription factors (Morris et al. 2005). Ketolideinduction has been described for erm(C) andinvolves promotion of frameshifting in theerm(C) leader (ermCL) mRNA, leading to by-pass of the ermCL stop codon, via rearrange-ment of the secondary mRNA structure, allow-ing expression of the downstream resistancegene (Gupta et al. 2013a).

    There are two families of macrolide effluxpumps with regulation that is at least in part,transcriptionally mediatedmef, a major-facil-

    O

    O OO

    O

    O

    ONO O-R2

    O-R3

    O-R4

    O-R1H3C

    Spiramycin

    Josamycin

    Kitasamycin

    Midecamycin

    Rosamicin Tilmicosin

    Tylosin

    Propionyl Propionyl

    CH3

    COCH3 COCH2CH(CH3)2

    Forosamine

    R1 R2 R3 R4

    H H

    H

    H

    H H

    H

    H

    H

    H

    H3CO

    O

    OH

    OO

    O

    O

    O

    NO

    O

    O O

    O

    O O O

    O

    O

    OOH

    R1H3C

    H3C

    R1

    Desosamine

    Mycaminose-mycarose

    Figure 2. Structures of 16-membered macrolides.

    Resistance to Macrolide Antibiotics in Public Health Pathogens

    Cite this article as Cold Spring Harb Perspect Med 2016;6:a025395 3

    ww

    w.p

    ersp

    ecti

    vesi

    nm

    edic

    ine.

    org

    on July 23, 2019 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from

    http://perspectivesinmedicine.cshlp.org/
  • C2610

    U2609

    U2609

    C2610

    A752

    ERY

    G2505

    Desosamine

    Desosamine

    C2611A2059

    A2058

    C2611

    C2C2 90 F

    F

    G2057

    A752

    A2058

    A752

    A2059

    Alkylarylgroup

    Alkylarylgroup

    C2611 A2058

    A752

    G2505A

    C

    B

    A2059

    C2610

    C2611

    Cladinose

    U2609

    A2058 A2059

    Desosamine

    G250523S rRNA

    ERYTELS