Biotechnological production and application of the antibiotic pimaricin: biosynthesis and its regulation

Abstract

Pimaricin (natamycin) is a small polyene macrolide antibiotic used worldwide. This efficient antimycotic and antiprotozoal agent, produced by several soil bacterial species of the genus Streptomyces, has found application in human therapy, in the food and beverage industries and as pesticide. It displays a broad spectrum of activity, targeting ergosterol but bearing a particular mode of action different to other polyene macrolides. The biosynthesis of this only antifungal agent with a GRAS status has been thoroughly studied, which has permitted the manipulation of producers to engineer the biosynthetic gene clusters in order to generate several analogues. Regulation of its production has been largely unveiled, constituting a model for other polyenes and setting the leads for optimizing the production of these valuable compounds. This review describes and discusses the molecular genetics, uses, mode of action, analogue generation, regulation and strategies for increasing pimaricin production yields.

Polyene macrolide biosynthesis in streptomycetes and related bacteria: recent advances from genome sequencing and experimental studies

“…Since the sequencing of the nystatin biosynthetic genes in S. noursei (Brautaset et al, 2000), at least three other closely related clusters have been found (Kim et al, 2009;Barke et al, 2012;Cui et al, 2015). Pimaricin is produced by S. natalensis, Streptomyces gilvosporus, Streptomyces lydicus and Streptomyces chattanoogensis (Aparicio et al, 2016). Genome sequences for S. natalensis (accession JRKI00000000.1) and S. chattanoogensis (Jiang et al, 2013) are now available.…”

“…Engineering of PKS and late genes has delivered several analogues of pimaricin, amphotericin B, nystatin, candicidin and rimocidin. Much of this work has been reviewed previously (Caffrey et al, 2008;Kong et al, 2013;Letek et al, 2014;Aparicio, 2016). Of the biosynthetically engineered polyene analogues, the most promising are those in which the free carboxyl group is replaced by a methyl group.…”

“…Regulation has been investigated for nystatin, tetramycin, and FR008 biosynthesis (Caffrey et al, 2008;Cui et al, 2015;Zhang et al, 2015), but the most detailed studies have been carried out on pimaricin (Aparicio et al, 2016).…”

“…In the pimaricin cluster, the PimR protein activates transcription of the gene for the pathway-specific activator PimM (Aparicio et al, 2016). This in turn regulates several promoters for PKS and late genes.…”

“…Improved analogues have been made by chemical methods and by genetic manipulation of producer micro-organisms (Cereghetti and Carreira, 2006). There have been several comprehensive reviews on polyene biosynthesis over the past few years (Caffrey et al, 2008;Kong et al, 2013;Letek et al, 2014;Aparicio et al, 2016). The field advances rapidly and genome sequences of many polyene producers are now available.…”