CbrA Is a Flavin Adenine Dinucleotide Protein That Modifies the Escherichia coli Outer Membrane and Confers Specific Resistance to Colicin M

Helbig, Stephanie; Hantke, Klaus; Ammelburg, Moritz; Braun, Volkmar

doi:10.1128/jb.00782-12

Cited by 10 publications

(17 citation statements)

References 48 publications

(54 reference statements)

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“…Thus, it was proposed that in the natural environment with a limited supply of nutrients, CbrA protects sensitive cells from colicin M synthesized by competitors. Furthermore, CbrC, which we also found to be induced by colicin M treatment, has been shown to protect against colicin E2 and also seems to be involved in alteration of outer membrane structure [41]. Our results indicate that subinhibitory concentrations of colicin M could induce protection against colicins.…”

Section: Resultssupporting

confidence: 60%

“…The two-component CreBC system positively controls transcription of cbrA . Recently, the CbrA protein was shown to protect against colicin M and osmotic shock, implying a function of CbrA in outer membrane structure [41]. Thus, it was proposed that in the natural environment with a limited supply of nutrients, CbrA protects sensitive cells from colicin M synthesized by competitors.…”

Section: Resultsmentioning

confidence: 99%

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Global transcriptional responses to the bacteriocin colicin M in Escherichia coli

Kamenšek

Žgur-Bertok

2013

BMC Microbiology

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BackgroundBacteriocins are protein antimicrobial agents that are produced by all prokaryotic lineages. Escherichia coli strains frequently produce the bacteriocins known as colicins. One of the most prevalent colicins, colicin M, can kill susceptible cells by hydrolyzing the peptidoglycan lipid II intermediate, which arrests peptidoglycan polymerization steps and provokes cell lysis. Due to the alarming rise in antibiotic resistance and the lack of novel antimicrobial agents, colicin M has recently received renewed attention as a promising antimicrobial candidate. Here the effects of subinhibitory concentrations of colicin M on whole genome transcription in E. coli were investigated, to gain insight into its ecological role and for purposes related to antimicrobial therapy.ResultsTranscriptome analysis revealed that exposure to subinhibitory concentrations of colicin M altered expression of genes involved in envelope, osmotic and other stresses, including genes of the CreBC two-component system, exopolysaccharide production and cell motility. Nonetheless, there was no induction of biofilm formation or genes involved in mutagenesis.ConclusionAt subinhibitory concentrations colicin M induces an adaptive response primarily to protect the bacterial cells against envelope stress provoked by peptidoglycan damage. Among the first induced were genes of the CreBC two-component system known to promote increased resistance against colicins M and E2, providing novel insight into the ecology of colicin M production in natural environments. While an adaptive response was induced nevertheless, colicin M application did not increase biofilm formation, nor induce SOS genes, adverse effects that can be provoked by a number of traditional antibiotics, providing support for colicin M as a promising antimicrobial agent.

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Section: Resultssupporting

confidence: 60%

Section: Resultsmentioning

confidence: 99%

Global transcriptional responses to the bacteriocin colicin M in Escherichia coli

Kamenšek

Žgur-Bertok

2013

BMC Microbiology

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“…In- terestingly, subinhibitory concentrations of colicin M induce the transcription of genes involved in adaptive responses, including the two-component CreBC system associated with increased resistance to some colicins (45). Recent studies have demonstrated that CbrA, being a nonessential protein, confers high resistance to colicin M and renders cells resistant to osmotic shock in a CreBCdependent manner (46). On the other hand, the overproduction of YieJ (formerly CbrC) enhances the tolerance of colicin E2 (a role previously assigned to CreD).…”

Section: Resultsmentioning

confidence: 99%

The Pseudomonas aeruginosa CreBC Two-Component System Plays a Major Role in the Response to β-Lactams, Fitness, Biofilm Growth, and Global Regulation

Zamorano

Moyá

Juan

et al. 2014

Antimicrob Agents Chemother

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bPseudomonas aeruginosa is a ubiquitous versatile environmental microorganism with a remarkable ability to grow under diverse environmental conditions. Moreover, P. aeruginosa is responsible for life-threatening infections in immunocompromised and cystic fibrosis patients, as the extraordinary capacity of this pathogen to develop antimicrobial resistance dramatically limits our therapeutic arsenal. Its large genome carries an outstanding number of genes belonging to regulatory systems, including multiple two-component sensor-regulator systems that modulate the response to the different environmental stimuli. Here, we show that one of two systems, designated CreBC (carbon source responsive) and BlrAB (␤-lactam resistance), might be of particular relevance. We first identified the stimuli triggering the activation of the CreBC system, which specifically responds to penicillin-binding protein 4 (PBP4) inhibition by certain ␤-lactam antibiotics. Second, through an analysis of a large comprehensive collection of mutants, we demonstrate an intricate interconnection between the CreBC system, the peptidoglycan recycling pathway, and the expression of the concerning chromosomal ␤-lactamase AmpC. Third, we show that the CreBC system, and particularly its effector inner membrane protein CreD, plays a major role in bacterial fitness and biofilm development, especially in the presence of subinhibitory concentrations of ␤-lactams. Finally, global transcriptomics reveals broad regulatory functions of CreBC in basic physiological aspects, particularly anaerobic respiration, in both the presence and absence of antibiotics. Therefore, the CreBC system is envisaged as a potentially interesting target for improving the efficacy of ␤-lactams against P. aeruginosa infections.

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“…However, the mechanism of action of the Cmi immunity protein still remains unknown. More recently, the overexpression of an E. coli gene named cbrA (formerly yidS) was shown to render cells specifically resistant to ColM (15). Based on the sequence similarities it exhibits with geranylgeranyl reductases (GGR) and other FAD-dependent oxidoreductases, Helbig et al suggested that the CbrA protein might function as a reductase of isoprenoid molecules.…”

Section: Introductionmentioning

confidence: 99%

CbrA Mediates Colicin M Resistance in Escherichia coli through Modification of Undecaprenyl-Phosphate-Linked Peptidoglycan Precursors

et al. 2020

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Colicin M is an enzymatic bacteriocin produced by some Escherichia coli strains which provokes cell lysis of competitor strains by hydrolysis of the cell-wall peptidoglycan lipid II precursor. The overexpression of a gene, cbrA (yidS), was shown to protect E. coli cells from the deleterious effects of this colicin but the underlying resistance mechanism was not established. We here report that a major structural modification of the undecaprenyl-phosphate carrier lipid and of its derivatives occurred in membranes of CbrA-overexpressing cells, which explains the acquisition of resistance towards this bacteriocin. Indeed, a main fraction of these lipids, including the lipid II peptidoglycan precursor, now display a saturated isoprene unit at the α-position, i.e. the unit closest to the colicin M cleavage site. Only unsaturated forms of these lipids were normally detectable in wild-type cells. In vitro and in vivo assays showed that colicin M did not hydrolyze α-saturated lipid II, clearly identifying this substrate modification as the resistance mechanism. These saturated forms of undecaprenyl-phosphate and lipid II remained substrates of the different enzymes participating in peptidoglycan biosynthesis and carrier lipid recycling, allowing this colicin M-resistance mechanism to occur without affecting this essential pathway. IMPORTANCE Overexpression of the chromosomal cbrA gene allows E. coli to resist to colicin M (ColM), a bacteriocin specifically hydrolyzing the lipid II peptidoglycan precursor of targeted cells. This resistance results from a CbrA-dependent modification of the precursor structure, i.e. reduction of the α-isoprenyl bond of C55-carrier lipid moiety that is proximal to ColM cleavage site. This modification, observed here for the first time in eubacteria, annihilates the ColM activity without affecting peptidoglycan biogenesis. These data, which further increase our knowledge on the substrate specificity of this colicin, highlight the capability of E. coli to generate reduced forms of C55-carrier lipid and its derivatives. Whether the function of this modification is only relevant with respect to ColM resistance is now questioned.

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CbrA Is a Flavin Adenine Dinucleotide Protein That Modifies the Escherichia coli Outer Membrane and Confers Specific Resistance to Colicin M

Abstract: ABSTRACTColicin M (Cma) is a protein toxin produced byEscherichia colithat kills sensitiveE. colicells by inhibiting murein biosynthesis in the periplasm. Recombinant plasmids carryingcbrA(… Show more

Cited by 10 publications

References 48 publications

Global transcriptional responses to the bacteriocin colicin M in Escherichia coli

Global transcriptional responses to the bacteriocin colicin M in Escherichia coli

The Pseudomonas aeruginosa CreBC Two-Component System Plays a Major Role in the Response to β-Lactams, Fitness, Biofilm Growth, and Global Regulation

CbrA Mediates Colicin M Resistance in Escherichia coli through Modification of Undecaprenyl-Phosphate-Linked Peptidoglycan Precursors

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