scholarly journals ABC Transporter DerAB of Lactobacillus casei Mediates Resistance against Insect-Derived Defensins

2020 ◽  
Vol 86 (14) ◽  
Author(s):  
Ainhoa Revilla-Guarinos ◽  
Qian Zhang ◽  
Christoph Loderer ◽  
Cristina Alcántara ◽  
Ariane Müller ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Antimicrobial Peptide ◽  
Abc Transporter ◽  
Lactobacillus Casei ◽  
Biological Effects ◽  
Gc Content ◽  
Resistance Response ◽  
Content Type ◽  
Antimicrobial Peptide Resistance ◽  
High Level

ABSTRACT Bce-like systems mediate resistance against antimicrobial peptides in Firmicutes bacteria. Lactobacillus casei BL23 encodes an “orphan” ABC transporter that, based on homology to BceAB-like systems, was proposed to contribute to antimicrobial peptide resistance. A mutant lacking the permease subunit was tested for sensitivity against a collection of peptides derived from bacteria, fungi, insects, and humans. Our results show that the transporter specifically conferred resistance against insect-derived cysteine-stabilized αβ defensins, and it was therefore renamed DerAB for defensin resistance ABC transporter. Surprisingly, cells lacking DerAB showed a marked increase in resistance against the lantibiotic nisin. This could be explained by significantly increased expression of the antimicrobial peptide resistance determinants regulated by the Bce-like systems PsdRSAB (formerly module 09) and ApsRSAB (formerly module 12). Bacterial two-hybrid studies in Escherichia coli showed that DerB could interact with proteins of the sensory complex in the Psd resistance system. We therefore propose that interaction of DerAB with this complex in the cell creates signaling interference and reduces the cell’s potential to mount an effective nisin resistance response. In the absence of DerB, this negative interference is relieved, leading to the observed hyperactivation of the Psd module and thus increased resistance to nisin. Our results unravel the function of a previously uncharacterized Bce-like orphan resistance transporter with pleiotropic biological effects on the cell. IMPORTANCE Antimicrobial peptides (AMPs) play an important role in suppressing the growth of microorganisms. They can be produced by bacteria themselves—to inhibit competitors—but are also widely distributed in higher eukaryotes, including insects and mammals, where they form an important component of innate immunity. In low-GC-content Gram-positive bacteria, BceAB-like transporters play a crucial role in AMP resistance but have so far been primarily associated with interbacterial competition. Here, we show that the orphan transporter DerAB from the lactic acid bacterium Lactobacillus casei is crucial for high-level resistance against insect-derived AMPs. It therefore represents an important mechanism for interkingdom defense. Furthermore, our results support a signaling interference from DerAB on the PsdRSAB module that might prevent the activation of a full nisin response. The Bce modules from L. casei BL23 illustrate a biological paradox in which the intrinsic nisin detoxification potential only arises in the absence of a defensin-specific ABC transporter.

scholarly journals Identification of a Genetic Locus Responsible for Antimicrobial Peptide Resistance inClostridium difficile

2010 ◽  
Vol 79 (1) ◽  
pp. 167-176 ◽  
Author(s):  
Shonna M. McBride ◽  
Abraham L. Sonenshein
Keyword(s):  
Antimicrobial Peptides ◽  
Antimicrobial Peptide ◽  
Abc Transporter ◽  
Genetic Locus ◽  
Polymyxin B ◽  
Transcriptional Analysis ◽  
Cationic Antimicrobial Peptide ◽  
Low Levels ◽  
Antimicrobial Peptide Resistance ◽  
Abc Transporter Genes

ABSTRACTClostridium difficilecauses chronic intestinal disease, yet little is understood about how the bacterium interacts with and survives in the host. To colonize the intestine and cause persistent disease, the bacterium must circumvent killing by host innate immune factors, such as cationic antimicrobial peptides (CAMPs). In this study, we investigated the effect of model CAMPs on growth and found thatC. difficileis not only sensitive to these compounds but also responds to low levels of CAMPs by expressing genes that lead to CAMP resistance. By plating the bacterium on medium containing the CAMP nisin, we isolated a mutant capable of growing in three times the inhibitory concentration of CAMPs. This mutant also showed increased resistance to the CAMPs gallidermin and polymyxin B, demonstrating tolerance to different types of antimicrobial peptides. We identified the mutated gene responsible for the resistance phenotype as CD1352. This gene encodes a putative orphan histidine kinase that lies adjacent to a predicted ABC transporter operon (CD1349 to CD1351). Transcriptional analysis of the ABC transporter genes revealed that this operon was upregulated in the presence of nisin in wild-type cells and was more highly expressed in the CD1352 mutant. The insertional disruption of the CD1349 gene resulted in significant decreases in resistance to the CAMPs nisin and gallidermin but not polymyxin B. Because of their role in cationic antimicrobial peptide resistance, we propose the designationcprABCfor genes CD1349 to CD1351 andcprKfor the CD1352 gene. These results provide the first evidence of aC. difficilegene associated with antimicrobial peptide resistance.

scholarly journals Deletion ofmtrCin Haemophilus ducreyi Increases Sensitivity to Human Antimicrobial Peptides and Activates the CpxRA Regulon

2011 ◽  
Vol 79 (6) ◽  
pp. 2324-2334 ◽  
Author(s):  
Sherri D. Rinker ◽  
Michael P. Trombley ◽  
Xiaoping Gu ◽  
Kate R. Fortney ◽  
Margaret E. Bauer
Keyword(s):  
Antimicrobial Peptides ◽  
Antimicrobial Peptide ◽  
Resistance Mechanism ◽  
Proton Motive Force ◽  
Human Infection ◽  
Motive Force ◽  
Haemophilus Ducreyi ◽  
Wild Type ◽  
Content Type ◽  
Antimicrobial Peptide Resistance

ABSTRACTHaemophilus ducreyiresists killing by antimicrobial peptides encountered during human infection, including cathelicidin LL-37, α-defensins, and β-defensins. In this study, we examined the role of the proton motive force-dependent multiple transferable resistance (MTR) transporter in antimicrobial peptide resistance inH. ducreyi. We found a proton motive force-dependent effect onH. ducreyi's resistance to LL-37 and β-defensin HBD-3, but not α-defensin HNP-2. Deletion of the membrane fusion protein MtrC renderedH. ducreyimore sensitive to LL-37 and human β-defensins but had relatively little effect on α-defensin resistance. ThemtrCmutant 35000HPmtrCexhibited phenotypic changes in outer membrane protein profiles, colony morphology, and serum sensitivity, which were restored to wild type bytrans-complementation withmtrC. Similar phenotypes were reported in acpxAmutant; activation of the two-component CpxRA regulator was confirmed by showing transcriptional effects on CpxRA-regulated genes in 35000HPmtrC. AcpxRmutant had wild-type levels of antimicrobial peptide resistance; acpxAmutation had little effect on defensin resistance but led to increased sensitivity to LL-37. 35000HPmtrCwas more sensitive than thecpxAmutant to LL-37, indicating that MTR contributed to LL-37 resistance independent of the CpxRA regulon. The CpxRA regulon did not affect proton motive force-dependent antimicrobial peptide resistance; however, 35000HPmtrChad lost proton motive force-dependent peptide resistance, suggesting that the MTR transporter promotes proton motive force-dependent resistance to LL-37 and human β-defensins. This is the first report of a β-defensin resistance mechanism inH. ducreyiand shows that LL-37 resistance inH. ducreyiis multifactorial.

scholarly journals Bcr1 Functions Downstream of Ssd1 To Mediate Antimicrobial Peptide Resistance in Candida albicans

2013 ◽  
Vol 12 (3) ◽  
pp. 411-419 ◽  
Author(s):  
Sook-In Jung ◽  
Jonathan S. Finkel ◽  
Norma V. Solis ◽  
Siyang Chaili ◽  
Aaron P. Mitchell ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Antimicrobial Peptides ◽  
Antimicrobial Peptide ◽  
Target Genes ◽  
Regulatory Protein ◽  
Homozygous Deletion ◽  
Plasma Membrane Permeability ◽  
Host Defense Peptides ◽  
Content Type ◽  
Antimicrobial Peptide Resistance

ABSTRACTIn order to colonize the host and cause disease,Candida albicansmust avoid being killed by host defense peptides. Previously, we determined that the regulatory protein Ssd1 governs antimicrobial peptide resistance inC. albicans. Here, we sought to identify additional genes whose products govern susceptibility to antimicrobial peptides. We discovered that abcr1Δ/Δ mutant, like thessd1Δ/Δ mutant, had increased susceptibility to the antimicrobial peptides, protamine, RP-1, and human β defensin-2. Homozygous deletion ofBCR1in thessd1Δ/Δ mutant did not result in a further increase in antimicrobial peptide susceptibility. Exposure of thebcr1Δ/Δ andssd1Δ/Δ mutants to RP-1 induced greater loss of mitochondrial membrane potential and increased plasma membrane permeability than with the control strains. Therefore, Bcr1 and Ssd1 govern antimicrobial peptide susceptibility and likely function in the same pathway. Furthermore,BCR1mRNA expression was downregulated in thessd1Δ/Δ mutant, and the forced expression ofBCR1in thessd1Δ/Δ mutant partially restored antimicrobial peptide resistance. These results suggest that Bcr1 functions downstream of Ssd1. Interestingly, overexpression of 11 known Bcr1 target genes in thebcr1Δ/Δ mutant failed to restore antimicrobial peptide resistance, suggesting that other Bcr1 target genes are likely responsible for antimicrobial peptide resistance. Collectively, these results demonstrate that Bcr1 functions downstream of Ssd1 to govern antimicrobial peptide resistance by maintaining mitochondrial energetics and reducing membrane permeabilization.

scholarly journals Induction of the Cpx Envelope Stress Pathway Contributes to Escherichia coli Tolerance to Antimicrobial Peptides

2013 ◽  
Vol 79 (24) ◽  
pp. 7770-7779 ◽  
Author(s):  
Bianca Audrain ◽  
Lionel Ferrières ◽  
Amira Zairi ◽  
Guillaume Soubigou ◽  
Curtis Dobson ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Antimicrobial Peptides ◽  
Antimicrobial Peptide ◽  
Polymyxin B ◽  
Genetic Response ◽  
Content Type ◽  
E Coli ◽  
Multiresistant Bacteria ◽  
Envelope Stress ◽  
Stress Pathway

ABSTRACTAntimicrobial peptides produced by multicellular organisms as part of their innate system of defense against microorganisms are currently considered potential alternatives to conventional antibiotics in case of infection by multiresistant bacteria. However, while the mode of action of antimicrobial peptides is relatively well described, resistance mechanisms potentially induced or selected by these peptides are still poorly understood. In this work, we studied the mechanisms of action and resistance potentially induced by ApoEdpL-W, a new antimicrobial peptide derived from human apolipoprotein E. Investigation of the genetic response ofEscherichia coliupon exposure to sublethal concentrations of ApoEdpL-W revealed that this antimicrobial peptide triggers activation of RcsCDB, CpxAR, and σEenvelope stress pathways. This genetic response is not restricted to ApoEdpL-W, since several other antimicrobial peptides, including polymyxin B, melittin, LL-37, and modified S4dermaseptin, also activate severalE. colienvelope stress pathways. Finally, we demonstrate that induction of the CpxAR two-component system directly contributes toE. colitolerance toward ApoEdpL-W, polymyxin B, and melittin. These results therefore show thatE. colisenses and responds to different antimicrobial peptides by activation of the CpxAR pathway. While this study further extends the understanding of the array of peptide-induced stress signaling systems, it also provides insight into the contribution of Cpx envelope stress pathway toE. colitolerance to antimicrobial peptides.

scholarly journals SSD1 Is Integral to Host Defense Peptide Resistance in Candida albicans

2008 ◽  
Vol 7 (8) ◽  
pp. 1318-1327 ◽  
Author(s):  
Kimberly D. Gank ◽  
Michael R. Yeaman ◽  
Satoshi Kojima ◽  
Nannette Y. Yount ◽  
Hyunsook Park ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Antimicrobial Peptides ◽  
Antimicrobial Peptide ◽  
Host Defense ◽  
Genomic Library ◽  
Inflammatory Responses ◽  
Host Defense Peptides ◽  
Antimicrobial Peptide Resistance ◽  
Null Mutants

ABSTRACT Candida albicans is usually a harmless human commensal. Because inflammatory responses are not normally induced by colonization, antimicrobial peptides are likely integral to first-line host defense against invasive candidiasis. Thus, C. albicans must have mechanisms to tolerate or circumvent molecular effectors of innate immunity and thereby colonize human tissues. Prior studies demonstrated that an antimicrobial peptide-resistant strain of C. albicans, 36082R, is hypervirulent in animal models versus its susceptible counterpart (36082S). The current study aimed to identify a genetic basis for antimicrobial peptide resistance in C. albicans. Screening of a C. albicans genomic library identified SSD1 as capable of conferring peptide resistance to a susceptible surrogate, Saccharomyces cerevisiae. Sequencing confirmed that the predicted translation products of 36082S and 36082R SSD1 genes were identical. However, Northern analyses corroborated that SSD1 is expressed at higher levels in 36082R than in 36082S. In isogenic backgrounds, ssd1Δ/ssd1Δ null mutants were significantly more susceptible to antimicrobial peptides than parental strains but had equivalent susceptibilities to nonpeptide stressors. Moreover, SSD1 complementation of ssd1Δ/ssd1Δ mutants restored parental antimicrobial peptide resistance phenotypes, and overexpression of SSD1 conferred enhanced peptide resistance. Consistent with these in vitro findings, ssd1 null mutants were significantly less virulent in a murine model of disseminated candidiasis than were their parental or complemented strains. Collectively, these results indicate that SSD1 is integral to C. albicans resistance to host defense peptides, a phenotype that appears to enhance the virulence of this organism in vivo.

scholarly journals The Maltose ABC Transporter in Lactococcus lactis Facilitates High-Level Sensitivity to the Circular Bacteriocin Garvicin ML

2012 ◽  
Vol 56 (6) ◽  
pp. 2908-2915 ◽  
Author(s):  
Christina Gabrielsen ◽  
Dag A. Brede ◽  
Pablo E. Hernández ◽  
Ingolf F. Nes ◽  
Dzung B. Diep
Keyword(s):  
Lactococcus Lactis ◽  
Abc Transporter ◽  
Specific Protein ◽  
Open Reading Frames ◽  
Content Type ◽  
Circular Bacteriocin ◽  
Carbohydrate Fermentation ◽  
High Level ◽  
Normal Sensitivity ◽  
Maltose Abc Transporter

ABSTRACTWe generated and characterized a series of spontaneous mutants ofLactococcus lactisIL1403 with average 6- to 11-fold-lowered sensitivities to the circular bacteriocin garvicin ML (GarML). Carbohydrate fermentation assays highlighted changes in carbohydrate metabolism, specifically loss of the ability to metabolize starch and maltose, in these mutants. PCR and sequencing showed that a 13.5-kb chromosomal deletion encompassing 12 open reading frames, mainly involved in starch and maltose utilization, had spontaneously occurred in the GarML-resistant mutants. Growth experiments revealed a correlation between sensitivity to GarML and carbon catabolite repression (CCR); i.e., sensitivity to GarML increased significantly when wild-type cells were grown on maltose and galactose as sole carbohydrates, an effect which was alleviated by the presence of glucose. Among the genes deleted in the mutants weremalEFG, which encode a CCR-regulated membrane-bound maltose ABC transporter. The complementation of mutants with these three genes recovered normal sensitivity to the bacteriocin, suggesting an essential role of the maltose ABC transporter in the antimicrobial activity of GarML. This notion was supported by the fact that the level of sensitivity to GarML was dose dependent, increasing with higher expression levels ofmalEFGover a 50-fold range. To our knowledge, this is the first time a specific protein complex has been demonstrated to be involved in sensitivity to a circular bacteriocin.

scholarly journals BceAB-type antibiotic resistance transporters appear to act by target protection of cell wall synthesis

2019 ◽  
Author(s):  
Carolin M Kobras ◽  
Hannah Piepenbreier ◽  
Jennifer Emenegger ◽  
Andre Sim ◽  
Georg Fritz ◽  
...  
Keyword(s):  
Cell Wall ◽  
Antimicrobial Peptides ◽  
Gc Content ◽  
Critical Factor ◽  
Peptide Antibiotics ◽  
Cell Wall Synthesis ◽  
Gram Positive ◽  
Gram Positive Bacteria ◽  
Lipid Ii ◽  
High Level

ABSTRACTResistance against cell wall-active antimicrobial peptides in bacteria is often mediated by transporters. In low GC-content Gram-positive bacteria, a wide-spread type of such transporters are the BceAB-like systems, which frequently provide a high level of resistance against peptide antibiotics that target intermediates of the lipid II cycle of cell wall synthesis. How a transporter can offer protection from drugs that are active on the cell surface, however, has presented researchers with a conundrum. Multiple theories have been discussed, ranging from removal of the peptides from the membrane, internalisation of the drug for degradation, to removal of the cellular target rather than the drug itself. To resolve this much-debated question, we here investigated the mode of action of the transporter BceAB of Bacillus subtilis. We show that it does not inactivate or import its substrate antibiotic bacitracin. Moreover, we present evidence that the critical factor driving transport activity is not the drug itself, but instead the concentration of drug-target complexes in the cell. Our results, together with previously reported findings, lead us to propose that BceAB-type transporters act by transiently freeing lipid II cycle intermediates from the inhibitory grip of antimicrobial peptides, and thus provide resistance through target protection of cell wall synthesis. Target protection has so far only been reported for resistance against antibiotics with intracellular targets, such as the ribosome. However, this mechanism offers a plausible explanation for the use of transporters as resistance determinants against cell wall-active antibiotics in Gram-positive bacteria where cell wall synthesis lacks the additional protection of an outer membrane.

scholarly journals Identification and Characterization of a Bacitracin Resistance Network in Enterococcus faecalis

2013 ◽  
Vol 58 (3) ◽  
pp. 1425-1433 ◽  
Author(s):  
Susanne Gebhard ◽  
Chong Fang ◽  
Aishath Shaaly ◽  
David J. Leslie ◽  
Marion R. Weimar ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Enterococcus Faecalis ◽  
Abc Transporter ◽  
Regulatory System ◽  
Proteome Analysis ◽  
Peptide Antibiotic ◽  
Content Type ◽  
Resistance Network ◽  
Two Component ◽  
Host Origin

ABSTRACTResistance ofEnterococcus faecalisagainst antimicrobial peptides, both of host origin and produced by other bacteria of the gut microflora, is likely to be an important factor in the bacterium's success as an intestinal commensal. The aim of this study was to identify proteins with a role in resistance against the model antimicrobial peptide bacitracin. Proteome analysis of bacitracin-treated and untreated cells showed that bacitracin stress induced the expression of cell wall-biosynthetic proteins and caused metabolic rearrangements. Among the proteins with increased production, an ATP-binding cassette (ABC) transporter with similarity to known peptide antibiotic resistance systems was identified and shown to mediate resistance against bacitracin. Expression of the transporter was dependent on a two-component regulatory system and a second ABC transporter, which were identified by genome analysis. Both resistance and the regulatory pathway could be functionally transferred toBacillus subtilis, proving the function and sufficiency of these components for bacitracin resistance. Our data therefore show that the two ABC transporters and the two-component system form a resistance network against antimicrobial peptides inE. faecalis, where one transporter acts as the sensor that activates the TCS to induce production of the second transporter, which mediates the actual resistance.

scholarly journals Complete Genome Sequence of Bacillus subtilis Strain MH1, Which Has a High Level of Bacteriocin-Like Activity, Isolated from Soil in Bangladesh

2018 ◽  
Vol 6 (25) ◽  
Author(s):  
Mohammad Shahnoor Hossain ◽  
Marufa Zerin Akhter ◽  
Muhammad Maqsud Hossain ◽  
M. Asaduzzaman Shishir ◽  
Shakila Nargis Khan ◽  
...  
Keyword(s):  
Bacillus Subtilis ◽  
Genome Sequence ◽  
Messenger Rna ◽  
Pathogenic Bacteria ◽  
Gc Content ◽  
Full Genome Sequence ◽  
Subtilis Strain ◽  
Bacteriocin Activity ◽  
Content Type ◽  
High Level

ABSTRACT Bacillus subtilis MH1 demonstrates a high level of bacteriocin activity against several pathogenic bacteria. We announce here the full-genome sequence of strain MH1, isolated from soil in Bangladesh. This genome length is 4,094,053 bp, with 43.5% GC content, 4,217 coding sequences (CDS), 10 rRNA, 84 tRNA, and 1 transfer-messenger RNA (tmRNA).

scholarly journals Genome Sequence Comparison of Staphylococcus aureus TX0117 and a Beta-Lactamase-Cured Derivative Shows Increased Cationic Peptide Resistance Accompanying Mutations in relA and mnaA

2020 ◽  
Vol 9 (18) ◽  
Author(s):  
Mia Jade Sales ◽  
George Sakoulas ◽  
Richard Szubin ◽  
Bernhard Palsson ◽  
Cesar Arias ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Peptide ◽  
Genome Sequence ◽  
Genome Assembly ◽  
Sequence Comparison ◽  
Beta Lactamase ◽  
Cationic Peptide ◽  
Content Type ◽  
Inoculum Effect ◽  
Antimicrobial Peptide Resistance

Staphylococcus aureus strain TX0117 is a methicillin-susceptible bacterium with type A beta-lactamase exhibiting a high cefazolin inoculum effect. TX0117 was cured of blaZ, yielding TX0117c with increased antimicrobial peptide resistance. The sequencing and genome assembly of TX0117 elucidate six mutations between TX0117 and TX0117c, including relA truncation and mnA_1 substitution.

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