Cellular accumulation of macrolide antibiotics. Intracellular bioactivity

Abstract

An extended classification of macrolides from the classical definition of Woodward presents a vast continuum of macrocyclic lactonic structures in which some molecules are mainly antibacterial (true macrolides) whereas others possess mainly immunosuppressant activity (FK 506, rapamycin) or antifungal activity with host cell inhibitory properties (bafilomycins, concannamycins). Traditional macrolide antibiotics are characterized by a 12- to 16-membered ring, macro-cyclic lactone nucleus, with few double-bonds, and substituted by several amino and/or neutral sugars. Over the past few decades, there has been continuous research into the development of new macrolide antibiotics by chemical modifications of the existing natural derivatives [1, 2]. This dynamic research has provided modern therapeutic agents, particularly the semi-synthetic derivatives of erythromycin A, either by adding new substituents, or introducing a nitrogen atom into the lactone (azalides), or, more recently, by withdrawing the L-cladinose at position 3 of the lactone ring and replacing it by a 3-keto function (ketolides). All these compounds display a substantially homogeneous antimicrobial spectrum and the capability to concentrate within host cells (the subject of this review). This property has been one major reason behind the search for new compounds targeting intracellular pathogens. Other possible consequences of the cellular accumulation of these drugs, particularly the modulation of various cell functions, are a further incentive for research in this field. A simplified chemical approach to the macrolide continuum is presented in Figure 1 [2, 3].