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 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 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 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 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 mSphere of Influence: Start with an Interesting Biological Phenomenon

mSphere ◽  
2019 ◽  
Vol 4 (3) ◽  
Author(s):  
Teresa O’Meara
Keyword(s):  
Candida Albicans ◽  
Single Cell Analysis ◽  
Homozygous Deletion ◽  
Functional Genomic ◽  
Cell Analysis ◽  
Biological Phenomenon ◽  
Content Type ◽  
Link Type ◽  
New Biology ◽  
Deletion Library

ABSTRACT Teresa O'Meara works in the field of functional genomics of Candida albicans, with a focus on host-pathogen interactions. In this mSphere of Influence article, she reflects on how papers entitled "Systematic Screens of a Candida albicans Homozygous Deletion Library Decouple Morphogenetic Switching and Pathogenicity" by S. M. Noble, S. French, L. A. Kohn, V. Chen, and A. D. Johnson (Nat Genet 42:590–598, 2010, https://doi.org/10.1038/ng.605) and "Exploring Quantitative Yeast Phenomics with Single-Cell Analysis of DNA Damage Foci" by E. B. Styles et al. (Cell Syst 3:264–277.e10, 2016, https://doi.org/10.1016/j.cels.2016.08.008) impacted her research and thinking through pioneering functional genomic screens. These articles show the power of combining defined mutant libraries with screens for interesting phenotypes to understand new biology.

scholarly journals Candida albicans Mucin Msb2 Is a Broad-Range Protectant against Antimicrobial Peptides

2013 ◽  
Vol 57 (8) ◽  
pp. 3917-3922 ◽  
Author(s):  
Marc Swidergall ◽  
Andreas M. Ernst ◽  
Joachim F. Ernst
Keyword(s):  
Candida Albicans ◽  
Antimicrobial Peptides ◽  
Tight Binding ◽  
Surface Protein ◽  
Protective Effects ◽  
Content Type ◽  
Histatin 5 ◽  
Growth Environment ◽  
Corynebacterium Pseudodiphtheriticum ◽  
Lipopeptide Antibiotic

ABSTRACTThe human fungal pathogenCandida albicansreleases a large glycofragment of the Msb2 surface protein (Msb2*) into the growth environment, which protects against the action of human antimicrobial peptides (AMPs) LL-37 and histatin-5. Quantitation of Msb2*/LL-37 interactions by microscale thermophoresis revealed high-affinity binding (dissociation constant [KD] = 73 nM), which was lost or greatly diminished by lack ofO-glycosylation or by Msb2* denaturation. Msb2* also interacted with human α- and β-defensins and protectedC. albicansagainst these AMPs. In addition, the lipopeptide antibiotic daptomycin was bound and inactivated by Msb2*, which prevented the killing of bacterial pathogensStaphylococcus aureus,Enterococcus faecalis, andCorynebacterium pseudodiphtheriticum. In coculturings or mixed biofilms ofS. aureuswithC. albicanswild-type but notmsb2mutant strains, the protective effects of Msb2* on the bactericidal action of daptomycin were demonstrated. These results suggest that tight binding of shed Msb2* to AMPs that occurs during bacterial coinfections withC. albicanscompromises antibacterial therapy by inactivating a relevant reserve antibiotic.

scholarly journals The Antimicrobial Peptides P-113Du and P-113Tri Function against Candida albicans

2016 ◽  
Vol 60 (10) ◽  
pp. 6369-6373 ◽  
Author(s):  
Guan-Yu Lin ◽  
Hsueh-Fen Chen ◽  
Yao-Peng Xue ◽  
Ying-Chieh Yeh ◽  
Chia-Lu Chen ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Antifungal Activity ◽  
Antimicrobial Peptides ◽  
Antifungal Agents ◽  
Low Ph ◽  
Planktonic Cells ◽  
Content Type ◽  
Peptide Derivatives ◽  
Helix Conformation ◽  
Α Helix

ABSTRACTTwo antimicrobial P-113 peptide derivatives, P-113Du and P-113Tri, were investigated in this study. Notably, P-113Du and P-113Tri contained significant fractions of α-helix conformation and were less sensitive to high salt and low pH than P-113. Moreover, compared to P-113, these peptides exhibited increased antifungal activity against planktonic cells, biofilm cells, and clinical isolates ofCandida albicansand non-albicans Candidaspp. These results suggest that P-113Du and P-113Tri are promising candidates for development as novel antifungal agents.

scholarly journals Rhb1 Regulates the Expression of Secreted Aspartic Protease 2 through the TOR Signaling Pathway in Candida albicans

2011 ◽  
Vol 11 (2) ◽  
pp. 168-182 ◽  
Author(s):  
Yu-Ting Chen ◽  
Chia-Ying Lin ◽  
Pei-Wen Tsai ◽  
Cheng-Yao Yang ◽  
Wen-Ping Hsieh ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Signaling Pathway ◽  
Virulence Factor ◽  
Nitrogen Availability ◽  
Target Genes ◽  
Small Gtpase ◽  
Aspartic Protease ◽  
Tor Signaling ◽  
Content Type

ABSTRACTCandida albicansis a major fungal pathogen in humans. InC. albicans, secreted aspartyl protease 2 (Sap2) is the most highly expressed secreted aspartic proteasein vitroand is a virulence factor. Recent research links the small GTPase Rhb1 toC. albicanstarget of rapamycin (TOR) signaling in response to nitrogen availability. The results of this study show that Rhb1 is related to cell growth through the control ofSAP2expression when protein is the major nitrogen source. This process involves various components of the TOR signaling pathway, including Tor1 kinase and its downstream effectors. TOR signaling not only controlsSAP2transcription but also affects Sap2 protein levels, possibly through general amino acid control. DNA microarray analysis identifies other target genes downstream of Rhb1 in addition toSAP2. These findings provide new insight into nutrients, Rhb1-TOR signaling, and expression ofC. albicansvirulence factor.

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 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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