Revealing second messenger functions in bacterial stress response, cell differentiation and natural product biosynthesis

Introduction

Sophisticated signalling systems enable bacteria to occupy almost every single niche on our planet. In such systems, second messengers are crucial information carriers that elicit cellular adaptation to diverse signals. Current dynamics in signalling research have led to the discovery of an exquisite collection of nucleotides that bacteria use as second messengers, including cyclic dimeric adenosine monophosphate (c-di-AMP). A unique feature of c-di-AMP is its essentiality, making it an attractive target for antibiotics.

Objectives

The main objective of this proposal is to uncover the full repertoire of c-di-AMP functions and metabolism in bacteria by using Streptomyces as a model.

Model Organism

Streptomyces are our most prolific antibiotic producers and represent an excellent system to study multicellular differentiation. They live in soil, where they encounter diverse environmental cues that trigger antibiotic production and a complex transition from multicellular filaments to spores.

Role of c-di-AMP

c-di-AMP enables Streptomyces to survive osmotic stress caused by rainfall and drought, but interferes with development. How c-di-AMP affects differentiation and how these bacteria adapt to stress signalled by c-di-AMP is unknown.

Proposed Research

Here, we propose that bacteria use a novel transmembrane signalling pathway to remodel their cell wall for surviving stress mediated by c-di-AMP.

Challenging Current Views

We will challenge the current view in the field by showing that the set of enzymes involved in c-di-AMP dynamics is larger than it is currently believed and we will identify new c-di-AMP effectors.

Exploration of c-di-AMP

Finally, we will explore the potential of c-di-AMP for manipulation of natural product biosynthesis and address the function of a linear di-AMP molecule that is new to signalling research.

Expected Outcomes

Our proposed research will not only lead to the discovery of fundamental new principles in bacterial signalling and differentiation but might also identify new cell wall associated targets for drug design and tools for triggering antibiotic biosynthesis.