Structural modifications and yield improvements of polyene macrolide antibiotics

Abstract

Polyene macrolide antibiotics, which selectively bind ergosterols in fungal membranes, are important antifungal agents for the treatment of both superficial and invasive fungal infections. But severe side effects, such as nephrotoxicity, are caused by their binding to cholesterol in mammalian membranes and undermine their therapeutic values. Nevertheless, because of their excellent fungicidal efficacy, broad spectrum of activities and minimal resistance development, polyene macrolide antibiotics continue to command interest. Therefore, the pharmacological and yield improvement of polyene macrolide antibiotics becomes urgent. In past few decades, much attention was paid on the genetic and chemical modifications of polyene macrolides, and a variety of genetic engineering strategies were applied to improve the yield of polyene macrolides. Based on the literature, we summarized the structural modifications of polyene macrolides in polyene region, polyol region, exocyclic carboxyl group and sugar moiety. The heptaene nystatin analog S44HP shows considerably higher antifungal activity than that of nystatin and equal to that of amphotericin B. While the exocyclic carboxyl modifications of polyene macrolides usually led to comparable or slightly improved antifungal activity and significantly reduced hemolytic toxicity, most of alterations in polyol region resulted in decreased antifungal activity and hemolytic toxicity. Furthermore, the polyene macrolides harboring a di–sugar moiety exhibited reduced hemolytic toxicity and improved water solubility, and the modifications in C3′ amino group or C2′ hydroxyl group considerably improved the pharmacological properties. Moreover, the action mechanisms and structure–activity relationship of polyene macrolide antibiotics were elucidated, according to the data of structural modifications. It indicated that the modifications in exocyclic carboxyl group, C3′ amino group or C2′ hydroxyl group disrupt the intramolecular polar interactions and thus favor a shift to an alternate conformer that selectively binds ergosterol rather than cholesterol. In addition, the strategies for yield improvement of polyene macrolide antibiotics were summarized, including the engineering of pathway-specific and pleiotropic regulatory genes, engineering of quorum–sensing communication, and optimization of precursor supply. Although transcriptional regulation has been investigated for amphotericin, nystatin and candicidin/FR–008 biosynthesis, most detailed genetic engineering strategies for yield improvement were only carried out on pimaricin. The yield of pimaricin was improved via the overexpression of pathway- specific or pleiotropic positive regulatory genes and GBL biosynthetic genes, the disruption of pathway-specific or pleiotropic negative regulatory genes and GBL receptor encoding genes, and the addition of inducing compounds or small molecular precursors. Finally, we pointed out the challenges and problems in the structural modifications and yield improvement of polyene macrolide antibiotics, such as the possibility to obtain more modified polene analogs with exocyclic carboxyl or C3′ amino group via genetic engineering, combinational strategies for further yield improvement of polyene macrolides, and so on.