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Earlier semi-synthetic studies of erythromycin A culminated in the discovery of two successful second generation macrolide antibiotics, azithromycin and clarithromycin, for the treatment of community-acquired bacterial infections. More recent structural modifications of erythromycin A have resulted in the discovery of novel ketolide antibiotics and new motilide prokinetic agents. This review is an account of the semi-synthetic developments from erythromycin A by chemical transformations.