Modeling the architecture of the regulatory system controlling methylenomycin production in Streptomyces coelicolor

Abstract

BackgroundThe antibiotic methylenomycin A is produced naturally by Streptomyces coelicolor A3(2), a model organism for streptomycetes. This compound is of particular interest to synthetic biologists because all of the associated biosynthetic, regulatory and resistance genes are located on a single cluster on the SCP1 plasmid, making the entire module easily transferable between different bacterial strains. Understanding further the regulation and biosynthesis of the methylenomycin producing gene cluster could assist in the identification of motifs that can be exploited in synthetic regulatory systems for the rational engineering of novel natural products and antibiotics.ResultsWe identify and validate a plausible architecture for the regulatory system controlling methylenomycin production in S. coelicolor using mathematical modeling approaches. Model selection via an approximate Bayesian computation (ABC) approach identifies three candidate model architectures that are most likely to produce the available experimental data, from a set of 48 possible candidates. Subsequent global optimization of the parameters of these model architectures identifies a single model that most accurately reproduces the dynamical response of the system, as captured by time series data on methylenomycin production. Further analyses of variants of this model architecture that capture the effects of gene knockouts also reproduce qualitative experimental results observed in mutant S. coelicolor strains.ConclusionsThe mechanistic mathematical model developed in this study recapitulates current biological knowledge of the regulation and biosynthesis of the methylenomycin producing gene cluster, and can be used in future studies to make testable predictions and formulate experiments to further improve our understanding of this complex regulatory system.

Triggering the expression of a silent gene cluster from genetically intractable bacteria results in scleric acid discovery

“…In S. coelicolor A3(2), these five genes are responsible for regulation of methylenomycin biosynthesis: mmyR and mmfR both code for TetR-like transcriptional repressors; mmfLHP are responsible for the biosynthesis of signalling molecules, known as methylenomycin furans (MMFs) that trigger production of the methylenomycin antibiotics 9. A mathematical model that explains in detail the methylenomycin regulatory system involving these five genes has been developed and matched with experimental data 20. In previous studies we have exploited this regulatory cassette and shown that inactivation of the mmyR -like transcriptional repressors is an effective approach for derepressing silent gene clusters in actinomycetes 10,12…”

A mechanistic model of the BLADE platform predicts performance characteristics of 256 different synthetic DNA recombination circuits

“…These results can provide answers to experimental hypotheses and hence inform the planning and enactment of subsequent experimental studies, saving time and resources. The dissemination of mathematical modelling approaches is important in establishing a wide-ranging archive of useful tools for the design and implementation of novel circuitry across synthetic biology [40][41][42][43][44][45]. In this paper, we present the first mechanistic mathematical model of the 2-input BLADE platform developed in [8].…”

A mechanistic model of the BLADE platform predicts performance characteristics of 256 different synthetic DNA recombination circuits

“…These results can provide answers to experimental hypotheses and hence inform the planning and enactment of subsequent experimental studies, saving time and resources. The dissemination of mathematical modelling approaches is important in establishing a wide-ranging archive of useful tools for the design and implementation of novel circuitry across synthetic biology [39][40][41][42][43][44]. In this paper, we present the first mechanistic mathematical model of the 2-input BLADE platform developed in [8].…”