Production of Prodiginines Is Part of a Programmed Cell Death Process in Streptomyces coelicolor

Abstract

Actinobacteria are prolific producers of antitumor antibiotics with antiproliferative activity, but why these bacteria synthetize metabolites with this bioactivity has so far remained a mystery. In this work we raised the hypothesis that under certain circumstances, production of antiproliferative agents could be part of a genetically programmed death of the producing organism. While programmed cell death (PCD) has been well documented when Streptomyces species switch from vegetative (nutrition) to aerial (reproduction) growth, lethal determinants are yet to be discovered. Using DNA-damaging prodiginines of Streptomyces coelicolor as model system, we revealed that, under certain conditions, their biosynthesis is always triggered in the dying zone of the mycelial network prior to morphological differentiation, right after an initial round of cell death. The programmed massive death round of the vegetative mycelium is absent in a prodiginine non-producer (ΔredD strain), and mutant complementation restored both prodiginine production and cell death. The redD null mutant of S. coelicolor also showed increased DNA, RNA, and proteins synthesis when most of the mycelium of the wild-type strain was dead when prodiginines accumulated. Moreover, addition of the prodiginine synthesis inhibitors also resulted in enhanced accumulation of viable filaments. Overall, our data enable us to propose a model where the time-space production of prodiginines is programmed to be triggered by the perception of dead cells, and their biosynthesis further amplifies the PCD process. As prodiginine production coincides with the moment S. coelicolor undergoes morphogenesis, the production of these lethal compounds might be used to eradicate the obsolete part of the population in order to provide nutrients for development of the survivors. Hence, next to weapons in competition between organisms or signals in inter- and intra-species communications, we propose a third role for antibiotics (in the literal meaning of the word ‘against life’) i.e., elements involved in self-toxicity in order to control cell proliferation, and/or for PCD associated with developmental processes.

A Challenging View: Antibiotics Play a Role in the Regulation of the Energetic Metabolism of the Producing Bacteria

“…This phenomenon of programmed cell death (PCD) is well documented in Streptomyces [23,24], and the lysis of vegetative mycelium has long been considered as a prerequisite for the emergence of aerial mycelium [25]. Indeed, the possible role of CDA in PCD in SC has already been evoked [18], and that of RED was recently demonstrated [26]. Antibiotics fulfilling similar functions as CDA and RED are classified as Type I antibiotics.…”

High-Resolution Analysis of the Peptidoglycan Composition in Streptomyces coelicolor

“…A major event associated with the lytic degradation of the cells is programmed cell death (PCD). PCD is likely a major hallmark of multicellularity (11) and has been described in the biofilm-forming Streptococcus (56) and Bacillus (57), in myxobacteria that form fruiting bodies (58), in the filamentous cyanobacteria (59,60), and in the branching Streptomyces (28,61,62). In streptomycetes, cell wall hydrolases support developmental processes such as branching and germination (21).…”

On the possible ecological roles of antimicrobials

“…In Streptomyces, a family of promiscuous receptors recognize both self-produced antibiotics and antibiotics produced by other strains and result in altered regulation of metabolite production and development (Wang et al, 2014;Xu et al, 2010). In S. coelicolor, the well-known red antibiotic prodigiosin was recently found to promote development by inducing 'programmed cell death' in a subset of cells possibly to provide nutrients to the surviving kin (Tenconi, Traxler, Hoebreck, Wezel, & Rigali, 2018). Similarly B. subtilis surfactins promote biofilm formation by their producers, but inhibit development in Streptomyces (Straight et al, 2006).…”