Biosynthesis of the acetyl-CoA carboxylase-inhibiting antibiotic, andrimid in Serratia is regulated by Hfq and the LysR-type transcriptional regulator, AdmX.

Miguel A Matilla,Veronika Nogellova,Bertrand Morel,George P C Salmond,Tino Krell

doi:10.1111/1462-2920.13241

Abstract

SummaryInfections due to multidrug‐resistant bacteria represent a major global health challenge. To combat this problem, new antibiotics are urgently needed and some plant‐associated bacteria are a promising source. The rhizobacterium Serratia plymuthica A153 produces several bioactive secondary metabolites, including the anti‐oomycete and antifungal haterumalide, oocydin A and the broad spectrum polyamine antibiotic, zeamine. In this study, we show that A153 produces a second broad spectrum antibiotic, andrimid. Using genome sequencing, comparative genomics and mutagenesis, we defined new genes involved in andrimid (adm) biosynthesis. Both the expression of the adm gene cluster and regulation of andrimid synthesis were investigated. The biosynthetic cluster is operonic and its expression is modulated by various environmental cues, including temperature and carbon source. Analysis of the genome context of the adm operon revealed a gene encoding a predicted LysR‐type regulator, AdmX, apparently unique to Serratia strains. Mutagenesis and gene expression assays demonstrated that AdmX is a transcriptional activator of the adm gene cluster. At the post‐transcriptional level, the expression of the adm cluster is positively regulated by the RNA chaperone, Hfq, in an RpoS‐independent manner. Our results highlight the complexity of andrimid biosynthesis – an antibiotic with potential clinical and agricultural utility.

Highlights

The discovery of antibiotics is one of the main milestones in the history of medicine
The observed antibacterial activity was not associated with the production of other known bioactive secondary metabolites produced by A153, namely oocydin A (Matilla et al, 2012) or zeamine (Hellberg et al, 2015)
During the in silico analysis of the A153 genome sequence (Matilla et al, 2016) we identified at least five candidate biosynthetic polyketide synthases (PKSs) and non-ribosomal peptide synthetases (NRPSs) gene clusters which could be responsible for the synthesis of the unknown antibacterial compound

Summary

Introduction

The discovery of antibiotics is one of the main milestones in the history of medicine. There is an urgent need to identify new antibiotics, but efforts focussed on discovery and development of new antibiotics have met with only limited success (Lewis, 2013; Pidot et al, 2014). New platforms for antibiotic discovery include the generation of synthetic antimicrobials and development of species-specific antibiotics (Fischbach and Walsh, 2009; Lewis, 2013; Liu et al, 2013; Pidot et al, 2014). Recent approaches to antibiotic discovery include screening of microbes from new ecological niches and attempts at exploitation of previously uncultured microbes (Fischbach and Walsh, 2009)

Results

Discussion

Conclusion