An auxin controls bacterial antibiotics production.

Miguel A Matilla,Bertrand Morel,Abdelali Daddaoua,Andrea Chini,Tino Krell

doi:10.1093/nar/gky766

Abstract

The majority of clinically used antibiotics originate from bacteria. As the need for new antibiotics grows, large-scale genome sequencing and mining approaches are being used to identify novel antibiotics. However, this task is hampered by the fact that many antibiotic biosynthetic clusters are not expressed under laboratory conditions. One strategy to overcome this limitation is the identification of signals that activate the expression of silent biosynthetic pathways. Here, we report the use of high-throughput screening to identify signals that control the biosynthesis of the acetyl-CoA carboxylase inhibitor antibiotic andrimid in the broad-range antibiotic-producing rhizobacterium Serratia plymuthica A153. We reveal that the pathway-specific transcriptional activator AdmX recognizes the auxin indole-3-acetic acid (IAA). IAA binding causes conformational changes in AdmX that result in the inhibition of the expression of the andrimid cluster and the suppression of antibiotic production. We also show that IAA synthesis by pathogenic and beneficial plant-associated bacteria inhibits andrimid production in A153. Because IAA is a signalling molecule that is present across all domains of life, this study highlights the importance of intra- and inter-kingdom signalling in the regulation of antibiotic synthesis. Our discovery unravels, for the first time, an IAA-dependent molecular mechanism for the regulation of antibiotic synthesis.

Highlights

Microbes represent a valuable source of antibiotics and around two-thirds of all naturally-derived antibiotics in clinical use are produced by bacteria [1]
We screened a collection of ∼1700 ligands that included (a) andrimid synthesis precursors; (b) 450 compounds that serve as bacterial carbon, nitrogen, phosphorous or sulphur sources; (c) approximately 1,200 compounds of a Natural Product-Like Library, which includes an array of natural product-like scaffolds [31] and (d) a collection of 43 natural and synthetic auxins (Supplementary Table S4)
Ligand free AdmX-ligand binding domain (LBD) showed a Tm of 56.5◦C and our screen detected three compounds that caused significant increases in Tm, namely 4-chloroindole-3-acetic acid (4ClIAA), indole-3-acetic acid (IAA) and indole-3-pyruvic acid (IPA) (Figure 1). 4ClIAA and IAA are naturally occurring auxins, while IPA is an auxin biosynthetic intermediate

Summary

Introduction

Microbes represent a valuable source of antibiotics and around two-thirds of all naturally-derived antibiotics in clinical use are produced by bacteria [1]. Because high metabolic costs are associated with the synthesis of these metabolites, their production is tightly regulated [3,5,9,13,14,15] This is reflected in the fact that many antibiotic biosynthetic clusters are cryptic and are not expressed under standard growth conditions [1,10,13,15] without the necessary environmental and physiological signals [5,9,10,13,14,15]. The signals recognized by most of the regulators involved in antibiotic production as well as their corresponding mechanisms of action remain largely unknown, which in turn hampers the discovery of novel antibiotics

Methods

Results

Conclusion