Johnny Silva Cancer Research

Erythromycin And Analogs

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Isolation of macrolides began in the 1950s with the discovery of pikromycin (90); the iso lation of numerous other macrolides quickly followed and the search for others continues today. Natural macrolides contain a highly substituted 12- to 16-member monocycle lactone ring, referred to as an aglycone, to which one or more deoxysugars are attached. Erythromycin, the first clinically used macrolide, was isolated in 1953 from Saccharoplyspora erythraea (formerly Streptomyces erythreus) (91). Erythromycin is a member of the 14-atom macrolide family and contains two sugar moieties: desosamine, an amino sugar, and cladinose (Fig. 6.8). It is a relatively broad-spectrum antibiotic with low toxicity, but it is also characterized by poor chemical stability, uncertain pharmacokinetics, and widespread bacterial resistance (32, 82). These negative qualities provided the impetus to search for erythromycin alternatives, both from natural sources and from semisynthetic modifications, that were improvements over erythromycin in one or more of the above categories. Several analogs (i.e., azithromycin and clarithromy-were noticeable improvements in all regards except resistance; bacteria were generally cross-resistant to erythromycin and its analogs. A new class of macrolide analogs, referred to as the ketolides, show great promise because of their increased activity both overall and against many erythromycin resistant bacteria (92-94).

8.1 Mechanism of Action

Macrolides bind to a region of 50S near the peptidyl transferase center and block the progress of the nascent peptide through the exit channel (14). Drug binding encompasses interactions to nucleotides from domain V (directly) and domain II (allosterically) of 23S rRNA (95). The dominant mechanism of resistance is through methylation of A2058 in domain V by the erm family of methyltrans-ferases, which confers resistance to macrolides, lincosamide, and group B streptogra-mines, a collection of structurally diverse antibiotics that are collectively referred to as MLS, antibiotics (57, 93). Cross-resistance arises from the sharing of a common binding site that includes interaction with A2058. The second most common form of erythromycin resistance comes from active efflux encoded for by mef genes (93). Also, clinical isolates

8 Erythromycin and Analogs

8 Erythromycin and Analogs