LmrR-mediated gene regulation of multidrug resistance in Lactococcus lactis

Agustiandari, Herfita; Peeters, Eveline; Wit, Janny G. de; Charlier, Daniël; Driessen, Arnold J. M.

doi:10.1099/mic.0.048025-0

Cited by 26 publications

(42 citation statements)

References 37 publications

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“…Interestingly, the VanR-DNA binding model is highly similar to the PadR-DNA interaction in which two dimers of PadR bind to a 40-bp DNA region in a way that both binding sites overlap in the center (47). In addition, the cooperative DNA binding mechanism also is shown for LmrR, where two LmrR dimers repress the transcription of lmrCD genes encoding a multidrug ABC transporter in L. lactis (24).…”

Section: Discussionmentioning

confidence: 82%

“…The proteins of subfamily 2 have a shorter C-terminal domain than subfamily 1 and contain 20 to 30 residues, such as LmrR from Lactococcus lactis (22) as well as Bacillus cereus PadR1 (bcPadR1) and bcPadR2 (23). Apart from their structures, physiological characteristics of the PadR, AphA, and LmrR regulators were intensively studied (21,(24)(25)(26). Intriguingly, the very first member of the PF03551 protein family, PadR, also deals with phenolic acids, albeit as a stress response regulator in B. subtilis (20,21).…”

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confidence: 99%

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Transcriptional Regulation of the Vanillate Utilization Genes ( vanABK Operon) of Corynebacterium glutamicum by VanR, a PadR-Like Repressor

et al. 2015

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P lant biomass is the main carbon supply in the soil. The plant cell wall is a lignocellulosic complex consisting of hydrophilic polymers, i.e., cellulose, hemicellulose, and pectin, along with the hydrophobic aromatic heteropolymer lignin (1, 2). The integrity of the plant cell wall depends on its lignin content, which is crosslinked to polysaccharides by hydroxycinnamic acids bridges, mainly ferulate (3-5). These feruloylated polysaccharides, especially the ferulate-arabinoxylan complex, serve as initiation sites for lignification in the cell walls (6, 7). Lignin is degraded by lignolytic enzymes, including lignin peroxidase, manganese peroxidase, or laccase, into ␤-aryl ether, di-aryl ether, and biphenyl, which are further catabolized to other aromatic compounds, such as vanillin and vanillate. Likewise, ferulate bound through ester linkages to hemicellulose is released by esterases and degrades to vanillin and vanillate (for a review, see references 4, 5, 8, 9, and 10).Phenolic acids released by degradation of lignin, e.g., ferulate or p-coumarate, are toxic for many Gram-positive bacteria, such as Bacillus subtilis, at low pH. Thus, there is a system for phenolic acid stress response which detoxifies phenolic acid by decarboxylation and generation of vinyl phenol derivatives (11). In contrast to B. subtilis, Corynebacterium glutamicum utilizes ferulate, vanillin, and vanillate derived from lignin degradation as a carbon source. Generally, aromatic compounds are channeled via gentisate, catechol, protocatechuate, 1,2,4-trihydroxybenzene, or phenylacetyl coenzyme A (phenylacetyl-CoA) intermediates into the central carbon metabolism of C. glutamicum (12). Ferulate is catabolized via vanillin and vanillate as the intermediate products to protocatechuate (3,4-dihydroxybenzoate) (see Fig. S1 in the supplemental material) (13). Protocatechuate is further metabolized in the aerobic ␤-ketoadipate pathway and finally flows into the carbon and energy cycle (14). So far, only the genes for degradation of vanillate are identified in C. glutamicum. Conversion of vanillate to protocatechuate is carried out by vanillate O-demethylase (see Fig. S1) (13). The vanillate O-demethylase enzyme has two subunits, which are encoded by vanA (NCgl2300) and vanB (NCgl2301) (13,15). In addition to vanillate O-demethylase, the vanillate utilization system consists of a vanillate transporter encoded by vanK (NCgl2302), which forms the vanABK operon along with vanA and vanB (16). Transcription of the vanABK operon is regulated by VanR (NCgl2299), which forms a divergon with the vanABK operon (12).VanR belongs to the PadR-like transcriptional regulator family (17). The PadR-like protein family (Pfam accession no. PF03551) contains 26 reported structures deposited in the Protein Data Bank (http://www.rcsb.org/). Generally, PadR-like regulators play an important role in their bacterial host, especially concerning virulence and stress. Structurally, PadR-type regulators contain a highly conserved N-terminal winged helix-turn-helix (wHTH)

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Section: Discussionmentioning

confidence: 82%

mentioning

confidence: 99%

Transcriptional Regulation of the Vanillate Utilization Genes ( vanABK Operon) of Corynebacterium glutamicum by VanR, a PadR-Like Repressor

et al. 2015

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“…A model PadR family transcriptional regulator is Lactococcus lactis LmrR (51). LmrR represses expression of lmrCD genes, which are cotranscribed with lmrR (52,53) and encode an ATP-binding cassette (ABC) transport system that confers multidrug resistance (52)(53)(54). Mutations in lmrR can lead to constitutive lmrCD expression and multidrug resistance (54).…”

Section: Resultsmentioning

confidence: 99%

Mutations Associated with Reduced Surotomycin Susceptibility in Clostridium difficile and Enterococcus Species

Adams

Mascio

et al. 2015

Antimicrob Agents Chemother

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bClostridium difficile infection (CDI) is an urgent public health concern causing considerable clinical and economic burdens. CDI can be treated with antibiotics, but recurrence of the disease following successful treatment of the initial episode often occurs. Surotomycin is a rapidly bactericidal cyclic lipopeptide antibiotic that is in clinical trials for CDI treatment and that has demonstrated superiority over vancomycin in preventing CDI relapse. Surotomycin is a structural analogue of the membraneactive antibiotic daptomycin. Previously, we utilized in vitro serial passage experiments to derive C. difficile strains with reduced surotomycin susceptibilities. The parent strains used included ATCC 700057 and clinical isolates from the restriction endonuclease analysis (REA) groups BI and K. Serial passage experiments were also performed with vancomycin-resistant and vancomycin-susceptible Enterococcus faecium and Enterococcus faecalis. The goal of this study is to identify mutations associated with reduced surotomycin susceptibility in C. difficile and enterococci. Illumina sequence data generated for the parent strains and serial passage isolates were compared. We identified nonsynonymous mutations in genes coding for cardiolipin synthase in C. difficile ATCC 700057, enoyl-(acyl carrier protein) reductase II (FabK) and cell division protein FtsH2 in C. difficile REA type BI, and a PadR family transcriptional regulator in C. difficile REA type K. Among the 4 enterococcal strain pairs, 20 mutations were identified, and those mutations overlap those associated with daptomycin resistance. These data give insight into the mechanism of action of surotomycin against C. difficile, possible mechanisms for resistance emergence during clinical use, and the potential impacts of surotomycin therapy on intestinal enterococci. C lostridium difficile is a Gram-positive anaerobic spore-forming bacterium and a causative agent of health care-associated infections (HAIs). C. difficile infection (CDI; alternatively called C. difficile-associated diarrhea) can occur after disruption of the normal microbiota of the gastrointestinal (GI) tract, thereby decreasing colonization resistance and allowing for C. difficile outgrowth (1). Toxin production by C. difficile can lead to severe disease. Over the last two decades, the incidence of CDI has increased dramatically, especially among elderly health care patients (1-3). A recent Centers for Disease Control and Prevention report on antibiotic resistance threats in the United States classifies C. difficile as an urgent public health threat, as it causes an estimated 250,000 infections per year, leading to an estimated 14,000 deaths and at least $1 billion in medical costs (2).CDI can be treated with antibiotics, but recurrence can occur after a successful therapy and is a persistent concern (3). Vancomycin, metronidazole, and the recently FDA-approved drug fidaxomicin are used to treat CDI (1, 3, 4). Surotomycin (CB-183,315) is a cyclic lipopeptide antibiotic and daptomycin analogue that...

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“…Some characterized PadR-like proteins play similar roles in the expression of resistance genes. Such is the case of LadR and LmrR that negatively regulate expression of multidrug efflux pumps in Listeria monocytogenes and Lactococcus lactis, respectively; this repression being released upon their interaction with some drugs (Agustiandari et al, 2011;Huillet et al, 2006). In Streptomyces, there are examples of repressors that inhibit expression of antibiotic resistance and export in antibiotic biosynthesis pathways; this repression being diminished by the antibiotic itself and/or some biosynthesis intermediates.…”

Section: Discussionmentioning

confidence: 99%

“…This is a quite recently identified family of regulatory proteins, named after the phenolic acid decarboxylation repressor of Bacillus subtilis, Pediococcus pentosaceus and Lactobacillus plantarum (Barthelmebs et al, 2000;Gury et al, 2004;Tran et al, 2008). To date, only a few members of this family have been characterized and these were shown to regulate diverse processes, including multidrug resistance, virulence, circadian rhythms and detoxification (Agustiandari et al, 2011;Barthelmebs et al, 2000;Gury et al, 2004;Huillet et al, 2006;Kovacikova et al, 2003). None of these characterized regulators belong to the actinomycetes group nor are they involved in antibiotic biosynthesis.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional regulation of mithramycin biosynthesis in Streptomyces argillaceus: dual role as activator and repressor of the PadR-like regulator MtrY

et al. 2015

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The mithramycin biosynthesis gene cluster of Streptomyces argillaceus ATCC 12956 contains 34 ORFs and includes two putative regulatory genes (mtmR and mtrY), which encode proteins of the SARP (Streptomyces antibiotic regulatory protein) and PadR transcriptional regulator families, respectively. MtmR was proposed to behave as a positive regulator of mithramycin biosynthesis. Inactivation and overexpression of mtrY indicated that it is also a positive regulator of mithramycin biosynthesis, being non-essential but required to maintain high levels of mithramycin production in the producer strain. Transcriptional analyses by reverse transcription PCR and quantitative realtime PCR of mithramycin genes, and promoter-probe assays in S. argillaceus polyketide synthase and regulatory mutants and the WT strain, and in the heterologous host Streptomyces albus, were carried out to analyse the role of MtmR and MtrY in the regulation of the mithramycin gene cluster. These experiments revealed that MtmR had a positive role, activating expression of at least six polycistronic units (mtmR-mtmE, mtmQ-mtmTII, mtmX-mtmY, mtmV-mtmTIII, mtmW-mtmMI and mtmGI-mtrB) and one monocistronic unit (mtmGII) in the mithramycin gene cluster. However, MtrY played a dual role in the mithramycin gene cluster: (i) repressing the expression of resistance genes and its coding gene itself by controlling the activity of the mtrYp promoter that directs expression of the regulator mtrY and resistance genes, with this repression being released in the presence of mithramycin; and (ii) enhancing the expression of mithramycin biosynthesis genes when mithramycin is present, by interacting with the mtmRp promoter that controls expression of the mtmR regulator, amongst others.

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LmrR-mediated gene regulation of multidrug resistance in Lactococcus lactis

Cited by 26 publications

References 37 publications

Transcriptional Regulation of the Vanillate Utilization Genes ( vanABK Operon) of Corynebacterium glutamicum by VanR, a PadR-Like Repressor

Transcriptional Regulation of the Vanillate Utilization Genes ( vanABK Operon) of Corynebacterium glutamicum by VanR, a PadR-Like Repressor

Mutations Associated with Reduced Surotomycin Susceptibility in Clostridium difficile and Enterococcus Species

Transcriptional regulation of mithramycin biosynthesis in Streptomyces argillaceus: dual role as activator and repressor of the PadR-like regulator MtrY

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