Small cationic antimicrobial peptides delocalize peripheral membrane proteins

Wenzel, Michaela; Chiriac, Alina Iulia; Otto, Andreas; Zweytick, Dagmar; May, Caroline; Schumacher, Catherine; Gust, Ronald; Albada, Bauke; Penkova, Maya; Krämer, Ute; Erdmann, Ralf; Metzler‐Nolte, Nils; Straus, Suzana K.; Bremer, Erhard; Becher, Dörte; Brötz‐Oesterhelt, Heike; Sahl, Hans‐Georg; Bandow, Julia E.

doi:10.1073/pnas.1319900111

Cited by 295 publications

(345 citation statements)

References 87 publications

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“…In mammals, cationic proteins produced by polymorphonuclear cells have been shown to display anti-microbial activity (Zeya & Spitznagel, 1966). Similar proteins with enzymatic activity have been reported in plants (Wenzela et al, 2014). The results presented here indicate that the effect of cationic proteins could also be mediated indirectly through the immune modulators (i.e., TNF-a).…”

Section: Discussionsupporting

confidence: 86%

T cell regulation byPhlomis lanataprotein extracts in mice

Karali

Georgescu

Pirintsos

et al. 2015

Pharmaceutical Biology

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Context: Phytopharmacology is a complex but very promising research area. The different plant parts and extraction methods may result in opposed effects. Phlomis species have been reported for both anti-inflammatory and tonic properties. Objective: The effect of Phlomis lanata Willd. (Lamiaceae) protein extracts on immune cell reactivity was studied in the experimental mouse model. Materials and methods: Protein extracts from P. lanata aerial parts were fractionated by Q-sepharose ion-exchange chromatography and applied to whole spleen cells or T-cell subsets at 5 mg/ml. Cell growth and cytokine production were evaluated after 4 and 2 d of culture using 3 H-thymidine-uptake and ELISA techniques, respectively. Results: Among the protein fractions tested, column wash proteins (W1) and the fraction eluted using 600 mM NaCl (F6) reduced by 76% and increased by 78% spleen cell proliferation, respectively. W1 suppressed proliferation of effector T-cells, but stimulated the growth of suppressor/regulatory cells by 62-148%. Although W1 stimulated IL-2 and IL-10 production from total spleen cells, it significantly increased IL-10 (50%) and reduced IL-2 (30-50%) production from T-cells, while TNF-a release was enhanced in CD25 + CD4 + by 92% and reduced by 50% in CD25 + CD8 + cells. F6 stimulated whole spleen cell growth, reduced proliferation of CD8 + and CD25 + cells by approximately 50%, while decreasing by 60-80% TNF-a production from CD25À and CD25 + CD8 + cells. Discussion and conclusion: The suppressive activity of W1 could be attributed to IL-10 and TNF-a, while the stimulatory effect of F6 could be attributed to the inhibition of T-regulatory cells. In the same plant, coexisting protein fractions induce both immunostimulatory and immunosuppressive activities.

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Section: Discussionsupporting

confidence: 86%

T cell regulation byPhlomis lanataprotein extracts in mice

Karali

Georgescu

Pirintsos

et al. 2015

Pharmaceutical Biology

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“…The outer leaflet of mammalian cell membranes is mainly composed of PC, which is charge-neutral at physiological pH. These phospholipids have been used in biophysical studies to study the interaction of a variety of AMPs with the lipid membrane, for example synthetic lipopeptides MX-2401 [35] and MSI-843 [36], the short cationic peptide MP196 [37], or the human antimicrobial peptide LL-37 [38].…”

Section: Resultsmentioning

confidence: 99%

Membrane interaction of a new synthetic antimicrobial lipopeptide sp-85 with broad spectrum activity

Grau-Campistany

Pujol

Marqués

et al. 2015

Colloids and Surfaces A: Physicochemical and Engineering Aspect

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ARTICLE IN PRESS• Sp-85 is a new synthetic antibiotic lipopeptide with broad spectrum activity.• Pressure-area curves of mixed monolayers show non-ideal mixing.• Binding to anionic liposomes results in fusion and leakage of aqueous contents.• TEM images of antibiotic-exposed bacteria show damaged membranes.• A mechanism of action based on bacterial membrane destabilization is proposed.g r a p h i c a l a b s t r a c t a r t i c l e i n f o a b s t r a c tAntimicrobial peptides offer a new class of therapeutic agents to which bacteria may not be able to develop genetic resistance, since their main activity is in the lipid component of the bacterial cell membrane. We have developed a series of synthetic cationic cyclic lipopeptides based on natural polymyxin, and in this work we explore the interaction of sp-85, an analog that contains a C12 fatty acid at the N-terminus and two residues of arginine. This analog has been selected from its broad spectrum antibacterial activity in the micromolar range, and it has a disruptive action on the cytoplasmic membrane of bacteria, as demonstrated by TEM. In order to obtain information on the interaction of this analog with membrane lipids, we have obtained thermodynamic parameters from mixed monolayers prepared with POPG and POPE/POPG (molar ratio 6:4), as models of Gram positive and Gram negative bacteria, respectively. Langmuir-Blodgett films have been extracted on glass plates and observed by confocal microscopy, and images are consistent with a strong destabilizing effect on the membrane organization induced by sp-85. The effect of sp-85 on the membrane is confirmed with unilamelar lipid vesicles of the same composition, where biophysical experiments based on fluorescence are indicative of membrane fusion and permeabilization starting at very low concentrations of peptide and only if anionic lipids are present. Overall, results described here provide strong evidence that the mode of action of sp-85 is the alteration of the bacterial membrane permeability barrier.

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“…The mevalonate pathway is required to make undecaprenyl pyrophosphate and lipid II (43). The consequence of this upregulation in the fabT deletion mutant strain might be increased production of lipid II, potentially leading to (i) in- creased resistance to cationic antimicrobial peptides (CAMPs) and lantibiotics that target lipid II (44)(45)(46) and (ii) higher levels of peptidoglycan (PG) and other envelope components that also are targets for CAMPs (47,48). The gene Spy_0124 (sloR), encoding a regulator involved in metal homeostasis, was also significantly upregulated by 10.3-fold in the fabT deletion mutant during mid-exponential phase at 35°C.…”

Section: Identification Of Acquired Polymorphisms In Serotype M1 Stramentioning

confidence: 99%

Genomic Landscape of Intrahost Variation in Group A Streptococcus: Repeated and Abundant Mutational Inactivation of the fabT Gene Encoding a Regulator of Fatty Acid Synthesis

et al. 2016

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dTo obtain new information about Streptococcus pyogenes intrahost genetic variation during invasive infection, we sequenced the genomes of 2,954 serotype M1 strains recovered from a nonhuman primate experimental model of necrotizing fasciitis. A total of 644 strains (21.8%) acquired polymorphisms relative to the input parental strain. The fabT gene, encoding a transcriptional regulator of fatty acid biosynthesis genes, contained 54.5% of these changes. The great majority of polymorphisms were predicted to deleteriously alter FabT function. Transcriptome-sequencing (RNA-seq) analysis of a wild-type strain and an isogenic fabT deletion mutant strain found that between 3.7 and 28.5% of the S. pyogenes transcripts were differentially expressed, depending on the growth temperature (35°C or 40°C) and growth phase (mid-exponential or stationary phase). Genes implicated in fatty acid synthesis and lipid metabolism were significantly upregulated in the fabT deletion mutant strain. FabT also directly or indirectly regulated central carbon metabolism genes, including pyruvate hub enzymes and fermentation pathways and virulence genes. Deletion of fabT decreased virulence in a nonhuman primate model of necrotizing fasciitis. In addition, the fabT deletion strain had significantly decreased survival in human whole blood and during phagocytic interaction with polymorphonuclear leukocytes ex vivo. We conclude that FabT mutant progeny arise during infection, constitute a metabolically distinct subpopulation, and are less virulent in the experimental models used here. Streptococcus pyogenes is a Gram-positive bacterium that causes a range of diseases in humans, including pharyngitis, superficial and deep skin infections, acute rheumatic fever, poststreptococcal glomerulonephritis, bacteremia, and necrotizing fasciitis ("flesh-eating disease") (1, 2). Globally, there are over 700 million group A streptococcus (GAS) infections annually (3). It has been estimated that 9,000 to 11,500 cases of invasive GAS disease occur each year in the United States, resulting in 1,000 to 1,800 deaths annually (4; http://www.cdc.gov). Rheumatic fever, necrotizing fasciitis, and toxic shock syndrome are responsible for the high morbidity and mortality rates due to GAS infections (5).Advances in DNA sequencing and related technologies have facilitated genome-wide dissection of genetic events involved in colonization (6), immune evasion (7), virulence (8-10), and the evolution and spread of highly virulent S. pyogenes clones (11-13). To advance our understanding of S. pyogenes molecular-pathogenesis events occurring during invasive infection, we performed whole-genome sequencing of 2,954 isolates recovered from a nonhuman primate model of necrotizing fasciitis. The resulting genome sequence data stimulated us to construct an isogenic fabT deletion mutant strain and to compare its global transcriptome and virulence attributes with those of the wild-type parental strain. MATERIALS AND METHODSBacterial strains and growth conditions. Escherichia coli strai...

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Small cationic antimicrobial peptides delocalize peripheral membrane proteins

Cited by 295 publications

References 87 publications

T cell regulation byPhlomis lanataprotein extracts in mice

T cell regulation byPhlomis lanataprotein extracts in mice

Membrane interaction of a new synthetic antimicrobial lipopeptide sp-85 with broad spectrum activity

Genomic Landscape of Intrahost Variation in Group A Streptococcus: Repeated and Abundant Mutational Inactivation of the fabT Gene Encoding a Regulator of Fatty Acid Synthesis

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