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Category: Bacterial Pathogenesis
Inhibitors of the 50S Ribosomal Subunit, Page 1 of 2
< Previous page | Next page > /docserver/preview/fulltext/10.1128/9781555817794/9781555812584_Chap18-1.gif /docserver/preview/fulltext/10.1128/9781555817794/9781555812584_Chap18-2.gifAbstract:
The macrolides are classified according to the number of atoms comprising the lactone ring in 12-, 14-, 15-, or 16-member macrolides, each of which has both chemical and biological differentiating characteristics. Target site modification has resulted in cross-resistance to the macrolides, lincosamides, and streptogramin B, the so-called MLSB phenotype. The natural macrolide antibiotics are isolated primarily from the genus Streptomyces. They are characterized by having antibacterial activity mostly against gram-positive bacteria. The macrolide antibiotics currently used in the United States are erythromycin and the semisynthetic derivatives of erythromycin A, i.e., clarithromycin, azithromycin, and dirithromycin. Constitutive resistance occurs when the methylating enzyme is produced constitutively, and inducible resistance occurs when the enzyme induction is effected by exposure of the organism to both 14-member ring and 15-member ring but not 16-member ring macrolides. The investigators conclude that the differences between the binding modes of macrolides, azalides, and ketolides reveal the contributions of the specific chemical modifications of the macrolides, and they explain the enhanced binding properties of the advanced compounds on this basis. The mode of action of the group B streptogramins is thought to be similar to that of 14-member ring macrolides, which sterically hinder the growth of the nascent peptide during early rounds of translation. Resistance to class B streptogramins takes place (i) by rRNA methylation catalyzed by a 23S rRNA methylase encoded in the erm genes, which also confers resistance to macrolides and lincosamides, or (ii) by an elimination of the hexadepsipeptide ring by specific lyases.
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Macrolide antibiotics subgrouped according to the size of the aglycon macrocyclic lactone ring. The 15-membered ring macrolides are named azalide. Taken from A. C. Bryskier and A. Denis, in W. Schönfeld and H. A. Kirst (ed.), Macrolide Antibiotics (Birkhaüser Verlag, Basel, Switzerland, 2002).
Macrolide antibiotics subgrouped according to the size of the aglycon macrocyclic lactone ring. The 15-membered ring macrolides are named azalide. Taken from A. C. Bryskier and A. Denis, in W. Schönfeld and H. A. Kirst (ed.), Macrolide Antibiotics (Birkhaüser Verlag, Basel, Switzerland, 2002).
Chemical structure of erythromycin A.
Chemical structure of erythromycin A.
Decomposition of erythromycin A under acidic conditions generates erythromycin 8,9-anhydro- 6,9-hemiketal and erythromycin 6,9,9,12-spiroketal.
Decomposition of erythromycin A under acidic conditions generates erythromycin 8,9-anhydro- 6,9-hemiketal and erythromycin 6,9,9,12-spiroketal.
Chemical structures of erythromycin A stearate and the ethylsuccinate ester of erythromycin A.
Chemical structures of erythromycin A stearate and the ethylsuccinate ester of erythromycin A.
Chemical structure of roxithromycin.
Chemical structure of roxithromycin.
Chemical synthesis of dirithromycin.
Chemical synthesis of dirithromycin.
Chemical structure of azithromycin.
Chemical structure of azithromycin.
Chemical structure of clarithromycin.
Chemical structure of clarithromycin.
Chemical structures of the 16- member macrolides josamycin, rokitamycin (semisynthetic), and spiramycin I (natural product).
Chemical structures of the 16- member macrolides josamycin, rokitamycin (semisynthetic), and spiramycin I (natural product).
Chemical structures of the macrolides midecamycin (natural) and miokamycin (semisynthetic).
Chemical structures of the macrolides midecamycin (natural) and miokamycin (semisynthetic).
Interaction of macrolides with the peptidyltransferase cavity. A chemical structure diagram of the macrolides (erythromycin, clarithromycin, and roxithromycin) is presented, showing the interactions of the reactive groups of the macrolides with the nucleotides of the peptidyltransferase cavity. Adapted from F. Schlünzen, R. Zarivach, J. Harms, A. Bashan, A. Tocilj, R. Albrecht, A. Yonath, and F. Franceschi, Nature 413:814–821, 1999, with permission from the publisher.
Interaction of macrolides with the peptidyltransferase cavity. A chemical structure diagram of the macrolides (erythromycin, clarithromycin, and roxithromycin) is presented, showing the interactions of the reactive groups of the macrolides with the nucleotides of the peptidyltransferase cavity. Adapted from F. Schlünzen, R. Zarivach, J. Harms, A. Bashan, A. Tocilj, R. Albrecht, A. Yonath, and F. Franceschi, Nature 413:814–821, 1999, with permission from the publisher.
All Erm methyltransferases methylate the same adenine residue, resulting in an MLSB phenotype.
All Erm methyltransferases methylate the same adenine residue, resulting in an MLSB phenotype.
(A) Secondary structure of E. coli 23S rRNA. (B and C) Enlargements of the hairpin 35 (B) and the central loop of domain V (C). The positions whose accessibility to modification by dimethyl sulfate is affected by macrolide antibiotics are circled (the position corresponding to ψ746 is protected by HMR3647 in the Thermus aquaticus ribosome). The nucleotides in domain V, whose mutations cause resistance to macrolides, are shown by black dots. The newly isolated macrolide resistance mutation in hairpin 35 is shown by an arrow. Posttranscriptional modifications are shown only for hairpin 35. Reprinted from L. Xiong, S. Shah, P. Mauvais, and A. S. Mankin, Mol. Microbiol. 31:633–639, 1999, with permission from the publisher.
(A) Secondary structure of E. coli 23S rRNA. (B and C) Enlargements of the hairpin 35 (B) and the central loop of domain V (C). The positions whose accessibility to modification by dimethyl sulfate is affected by macrolide antibiotics are circled (the position corresponding to ψ746 is protected by HMR3647 in the Thermus aquaticus ribosome). The nucleotides in domain V, whose mutations cause resistance to macrolides, are shown by black dots. The newly isolated macrolide resistance mutation in hairpin 35 is shown by an arrow. Posttranscriptional modifications are shown only for hairpin 35. Reprinted from L. Xiong, S. Shah, P. Mauvais, and A. S. Mankin, Mol. Microbiol. 31:633–639, 1999, with permission from the publisher.
Cleavage of the lactone ring of erythronolide A, catalyzed by esterases.
Cleavage of the lactone ring of erythronolide A, catalyzed by esterases.
Chemical structures of telithromycin, ABT-773, and TEA-0777. For comparison, the chemical structures of erythromycin A and clarithromycin are also shown. Note that in these structures the CH3 (methyl, Me) and CH2CH3 (ethyl) groups are represented by a line above or below the plane of the molecule.
Chemical structures of telithromycin, ABT-773, and TEA-0777. For comparison, the chemical structures of erythromycin A and clarithromycin are also shown. Note that in these structures the CH3 (methyl, Me) and CH2CH3 (ethyl) groups are represented by a line above or below the plane of the molecule.
Chemical structures of clindamycin and lincomycin.
Chemical structures of clindamycin and lincomycin.
Interactions of clindamycin with the peptidyltransferase cavity. (a) Chemical structure diagram of clindamycin showing the interactions (arrows) of its reactive groups with the nucleotides of the peptidyltransferase cavity. Arrows between two chemical moieties indicate that the two groups are less than 4.4 Å apart. (b) Secondary structure of the peptidyltransferase ring of D. radiodurans, showing the nucleotides involved in the interaction with clindamycin. Reprinted from F. Schlünzen, R. Zarivach, J. Harms, A. Bashan, A. Tocilj, R. Albrecht, A. Yonath, and F. Franceschi, Nature 413:814–821, 1999, with permission from the publisher.
Interactions of clindamycin with the peptidyltransferase cavity. (a) Chemical structure diagram of clindamycin showing the interactions (arrows) of its reactive groups with the nucleotides of the peptidyltransferase cavity. Arrows between two chemical moieties indicate that the two groups are less than 4.4 Å apart. (b) Secondary structure of the peptidyltransferase ring of D. radiodurans, showing the nucleotides involved in the interaction with clindamycin. Reprinted from F. Schlünzen, R. Zarivach, J. Harms, A. Bashan, A. Tocilj, R. Albrecht, A. Yonath, and F. Franceschi, Nature 413:814–821, 1999, with permission from the publisher.
Mechanism whereby clindamycin and lincomycin are converted to lincomycin and clindamycin 3-(5'-adenylate) by LinB in the presence of ATP and MgCl2.
Mechanism whereby clindamycin and lincomycin are converted to lincomycin and clindamycin 3-(5'-adenylate) by LinB in the presence of ATP and MgCl2.
Chemical structures of natural pristinamycin IA and IIA. The components of pristinamycin are indicated (see the text for an explanation). Note that the Cahn- Ingold-Prelog system is used to denote the configuration of the chiral centers, and an ethyl group is represented by a line in the aminobutyric acid moiety. The two rings that are part of the macrolactone of pristinamycin IIA (on the right) are also indicated.
Chemical structures of natural pristinamycin IA and IIA. The components of pristinamycin are indicated (see the text for an explanation). Note that the Cahn- Ingold-Prelog system is used to denote the configuration of the chiral centers, and an ethyl group is represented by a line in the aminobutyric acid moiety. The two rings that are part of the macrolactone of pristinamycin IIA (on the right) are also indicated.
Chemical structures of quinupristin and dalfopristin. An acetyltransferase inactivates dalfopristin (see the text for details). The position of the modified hydroxyl group in dalfopristin is indicated by the asterisk.
Chemical structures of quinupristin and dalfopristin. An acetyltransferase inactivates dalfopristin (see the text for details). The position of the modified hydroxyl group in dalfopristin is indicated by the asterisk.
Secondary structure of the peptidyltransferase loop in domain V of 23S rRNA. The mutated position in S. pneumoniae BM4455 is indicated by a square. The positions of the other binding sites of streptogramins (A2058, A2503, and U2504) are indicated by circles. Nucleotide sequence and numbering are those of E. coli 23S rRNA, and the corresponding S. pneumoniae numbering is given in parentheses. Reprinted from F. Depardieu and P. Courvalin, Antimicrob. Agents Chemother. 45:319–323, 2001, with permission from the American Society for Microbiology.
Secondary structure of the peptidyltransferase loop in domain V of 23S rRNA. The mutated position in S. pneumoniae BM4455 is indicated by a square. The positions of the other binding sites of streptogramins (A2058, A2503, and U2504) are indicated by circles. Nucleotide sequence and numbering are those of E. coli 23S rRNA, and the corresponding S. pneumoniae numbering is given in parentheses. Reprinted from F. Depardieu and P. Courvalin, Antimicrob. Agents Chemother. 45:319–323, 2001, with permission from the American Society for Microbiology.
Generic and common trade names of macrolides, the preparations available, and manufacturers in the United States
Generic and common trade names of macrolides, the preparations available, and manufacturers in the United States
Generic and common trade names of lincosamides, the preparations available, and manufacturers in the United States
Generic and common trade names of lincosamides, the preparations available, and manufacturers in the United States