The antibiotic planosporicin coordinates its own production in the actinomycete Planomonospora alba

Abstract

Planosporicin is a ribosomally synthesized, posttranslationally modified peptide lantibiotic produced by the actinomycete Planomonospora alba. It contains one methyl-lanthionine and four lanthionine bridges and inhibits cell wall biosynthesis in other Gram-positive bacteria probably by binding to lipid II, the immediate precursor for cell wall biosynthesis. Planosporicin production, which is encoded by a cluster of 15 genes, is confined to stationary phase in liquid culture and to the onset of morphological differentiation when P. alba is grown on agar. This growth phase-dependent gene expression is controlled transcriptionally by three pathway-specific regulatory proteins: an extracytoplasmic function σ factor (PspX), its cognate anti-σ factor (PspW), and a transcriptional activator (PspR) with a C-terminal helix-turn-helix DNA-binding domain. Using mutational analysis, S1 nuclease mapping, quantitative RT-PCR, and transcriptional fusions, we have determined the direct regulatory dependencies within the planosporicin gene cluster and present a model in which subinhibitory concentrations of the lantibiotic function in a feed-forward mechanism to elicit high levels of planosporicin production. We show that in addition to acting as an antibiotic, planosporicin can function as an extracellular signaling molecule to elicit precocious production of the lantibiotic, presumably ensuring synchronous and concerted lantibiotic biosynthesis in the wider population and, thus, the production of ecologically effective concentrations of the antibiotic.

Prospecting for new bacterial metabolites: a glossary of approaches for inducing, activating and upregulating the biosynthesis of bacterial cryptic or silent natural products

“…Heterologous expression provides a useful, but sometimes challenging approach to enable the production of a single series of compounds from a cryptic cluster of interest thereby enabling the compound's identification; such an approach represents the only way for accessing the chemical pallet of unculturable microbes. Metabolic switching in actinomycetes and the regulation of secondary metabolite production is highly complex and varied [120][121][122] and such expression systems often require careful tailoring in order to enable production of a specific compound of interest; this can often be a bottle-neck to the discovery process.…”

Engineering microbial hosts for production of bacterial natural products

“…155 A group of alternative sigma factors particularly enriched in actinomycetes is the extracytoplasmic (ECF) sigma factor family, which mediates global transcriptome changes in response to environmental and physiological stimuli. ECF sigma factors have been shown to be required for the expression of key biosynthetic genes and the production of lantibiotics in rare actinomycetes 156, 157 and antimycins in S. albus . 158 In Planomonospora alba , introducing a second copy of ECF sigma factor pspX increased planosporicin production, while disruption of its cognate anti-sigma factor significantly increased the expression of the target biosynthetic genes and led to constitutive production of the lantibiotic.…”

“…158 In Planomonospora alba , introducing a second copy of ECF sigma factor pspX increased planosporicin production, while disruption of its cognate anti-sigma factor significantly increased the expression of the target biosynthetic genes and led to constitutive production of the lantibiotic. 157 Interestingly, ECF σ 25 in S. avermitilis differentially regulates production of two macrolides oligomycin and avermectin, where overexpression of sig25 increases oligomycin production but decreases avermectin titer. 159 Given that σ 25 directly binds to promoter regions of oligomycin biosynthetic genes, it is likely that the associated reduction in avermectin production is due to competition for common precursors.…”

Lantibiotics produced by Actinobacteria and their potential applications (a review)

“…Planosporicin production, which is encoded by a cluster of 15 genes, is confined to the stationary phase of growth in broth and to the onset of morphological differentiation when Planomonospora spp. are grown on solid medium [51]. Despite sharing remarkable structural and antibacterial spectrum similarities, inhibiting important Gram-positive pathogens, planosporicin exhibited a less potent antimicrobial activity than microbisporicin/NAI-117 against all tested micro-organisms, including staphylococci, streptococci and enterococci, among others [15].…”