The MarR-Type Regulator MalR Is Involved in Stress-Responsive Cell Envelope Remodeling in Corynebacterium glutamicum.

Max Hünnefeld,Julia Frunzke,Jörn Kalinowski,Marcus Persicke

doi:10.3389/fmicb.2019.01039

Abstract

It is the enormous adaptive capacity of microorganisms, which is key to their competitive success in nature, but also challenges antibiotic treatment of human diseases. To deal with a diverse set of stresses, bacteria are able to reprogram gene expression using a wide variety of transcription factors. Here, we focused on the MarR-type regulator MalR conserved in the Corynebacterineae, including the prominent pathogens Corynebacterium diphtheriae and Mycobacterium tuberculosis. In several corynebacterial species, the malR gene forms an operon with a gene encoding a universal stress protein (uspA). Chromatin affinity purification and sequencing (ChAP-Seq) analysis revealed that MalR binds more than 60 target promoters in the C. glutamicum genome as well as in the large cryptic prophage CGP3. Overproduction of MalR caused severe growth defects and an elongated cell morphology. ChAP-Seq data combined with a global transcriptome analysis of the malR overexpression strain emphasized a central role of MalR in cell envelope remodeling in response to environmental stresses. For example, prominent MalR targets are involved in peptidoglycan biosynthesis and synthesis of branched-chain fatty acids. Phenotypic microarrays suggested an altered sensitivity of a ΔmalR mutant toward several β-lactam antibiotics. Furthermore, we revealed MalR as a repressor of several prophage genes, suggesting that MalR may be involved in the control of stress-responsive induction of the large CGP3 element. In conclusion, our results emphasize MalR as a regulator involved in stress-responsive remodeling of the cell envelope of C. glutamicum and suggest a link between cell envelope stress and the control of phage gene expression.

Highlights

In almost every natural habitat, a high number of microbial species coexist and compete for space and nutrients
In the genome of C. glutamicum ATCC 13032, malR is organized in an operon with a gene encoding a universal stress protein and is divergently located to a small hypothetical protein, followed by an operon coding for a penicillin-binding protein and two putative membrane proteins (Figure 1; PfeiferSancar et al, 2013)
We provided comprehensive insights into the complex regulon of the MarR-type regulator MalR in C. glutamicum

Summary

Introduction

In almost every natural habitat, a high number of microbial species coexist and compete for space and nutrients. Following studies showed that E. coli MarR is a transcriptional repressor of genes conferring resistance toward different antibiotics, organic solvents and lipophilic, mainly phenolic compounds (Alekshun and Levy, 1999). The regulatory responses modulated by MarR-type regulators were grouped into three general categories (Wilkinson and Grove, 2006), including (i) environmental stress responses (e.g., triggered by antibiotics) (Poole et al, 1996; Srikumar et al, 2000; Spory et al, 2002), (ii) regulation of virulence genes (Lee et al, 2003; Rouanet et al, 2004), and (iii) degradation of lipophilic (often aromatic) compounds (Providenti and Wyndham, 2001; Galán et al, 2003). The dissociation of the MarR dimer from its genetic target is triggered by ligand binding [e.g., antibiotics, salicylates, and lipophilic compounds (Kumarevel, 2012)], but examples exist where the binding of ligands fosters the association to DNA targets (Egland and Harwood, 1999; Providenti and Wyndham, 2001)

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Conclusion