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Hans-georg Sahl - One of the best experts on this subject based on the ideXlab platform.
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Proteomic Response of Bacillus subtilis to Lantibiotics Reflects Differences in Interaction with the Cytoplasmic Membrane
2016Co-Authors: Hans-georg Sahl, Julia E. BAbstract:Mersacidin, gallidermin, and nisin are Lantibiotics, antimicrobial peptides containing lanthionine. They show potent antibacte-rial activity. All three interfere with cell wall biosynthesis by binding lipid II, but they display different levels of interaction with the cytoplasmic membrane. On one end of the spectrum, mersacidin interferes with cell wall biosynthesis by binding lipid II without integrating into bacterial membranes. On the other end of the spectrum, nisin readily integrates into membranes, where it forms large pores. It destroys the membrane potential and causes leakage of nutrients and ions. Gallidermin, in an intermedi-ate position, also readily integrates into membranes. However, pore formation occurs only in some bacteria and depends on membrane composition. In this study, we investigated the impact of nisin, gallidermin, andmersacidin on cell wall integrity, membrane pore formation, and membrane depolarization in Bacillus subtilis. The impact of the Lantibiotics on the cell envelope was correlated to the proteomic response they elicit in B. subtilis. By drawing on a proteomic response library, including other envelope-targeting antibiotics such as bacitracin, vancomycin, gramicidin S, or valinomycin, YtrE could be identified as the most reliable marker protein for interfering with membrane-bound steps of cell wall biosynthesis. NadE and PspA were identified as markers for antibiotics interacting with the cytoplasmic membrane. Over the last decades, bacteria have demonstrated their im-pressive ability to adapt to changing environmental condi-tions by rapidly developing and accumulating antibiotic resis-tances. Helped by an extensive use of antibiotics in health care an
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family of class i Lantibiotics from actinomycetes and improvement of their antibacterial activities
ACS Chemical Biology, 2015Co-Authors: Sonia I Maffioli, Hans-georg Sahl, Daniela Münch, Paolo Monciardini, Bruno Catacchio, Carlo Mazzetti, Cristina Brunati, Stefano DonadioAbstract:Lantibiotics, an abbreviation for "lanthionine-containing antibiotics", interfere with bacterial metabolism by a mechanism not exploited by the antibiotics currently in clinical use. Thus, they have aroused interest as a source for new therapeutic agents because they can overcome existing resistance mechanisms. Starting from fermentation broth extracts preselected from a high-throughput screening program for discovering cell-wall inhibitors, we isolated a series of related class I Lantibiotics produced by different genera of actinomycetes. Analytical techniques together with explorative chemistry have been used to establish their structures: the newly described compounds share a common 24 aa sequence with the previously reported lantibiotic planosporicin (aka 97518), differing at positions 4, 6, and 14. All of these compounds maintain an overall -1 charge at physiological pH. While all of these Lantibiotics display modest antibacterial activity, their potency can be substantially modulated by progressively eliminating the negative charges, with the most active compounds carrying basic amide derivatives of the two carboxylates originally present in the natural compounds. Interestingly, both natural and chemically modified Lantibiotics target the key biosynthetic intermediate lipid II, but the former compounds do not bind as effectively as the latter in vivo. Remarkably, the basic derivatives display an antibacterial potency and a killing effect similar to those of NAI-107, a distantly related actinomycete-produced class I lantibiotic which lacks altogether carboxyl groups and which is a promising clinical candidate for treating Gram-positive infections caused by multi-drug-resistant pathogens.
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Proteomic Response of Bacillus subtilis to Lantibiotics Reflects Differences in Interaction with the Cytoplasmic Membrane
Antimicrobial agents and chemotherapy, 2012Co-Authors: Michaela Wenzel, Hans-georg Sahl, Bastian Kohl, Daniela Münch, Nadja Raatschen, H. Bauke Albada, Leendert W. Hamoen, Nils Metzler-nolte, Julia E. BandowAbstract:Mersacidin, gallidermin, and nisin are Lantibiotics, antimicrobial peptides containing lanthionine. They show potent antibacterial activity. All three interfere with cell wall biosynthesis by binding lipid II, but they display different levels of interaction with the cytoplasmic membrane. On one end of the spectrum, mersacidin interferes with cell wall biosynthesis by binding lipid II without integrating into bacterial membranes. On the other end of the spectrum, nisin readily integrates into membranes, where it forms large pores. It destroys the membrane potential and causes leakage of nutrients and ions. Gallidermin, in an intermediate position, also readily integrates into membranes. However, pore formation occurs only in some bacteria and depends on membrane composition. In this study, we investigated the impact of nisin, gallidermin, and mersacidin on cell wall integrity, membrane pore formation, and membrane depolarization in Bacillus subtilis. The impact of the Lantibiotics on the cell envelope was correlated to the proteomic response they elicit in B. subtilis. By drawing on a proteomic response library, including other envelope-targeting antibiotics such as bacitracin, vancomycin, gramicidin S, or valinomycin, YtrE could be identified as the most reliable marker protein for interfering with membrane-bound steps of cell wall biosynthesis. NadE and PspA were identified as markers for antibiotics interacting with the cytoplasmic membrane.
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Expression of the Lantibiotic Mersacidin in Bacillus amyloliquefaciens FZB42
2011Co-Authors: Anna Maria Herzner, Hans-georg Sahl, Jasmin Dischinger, Christiane Szekat, Michaele Josten, Stephanie Schmitz, Anja Yakéléba, Ricarda Reinartz, Andrea Jansen, Jörn PielAbstract:Lantibiotics are small peptide antibiotics that contain the characteristic thioether amino acids lanthionine and methyllanthionine. As ribosomally synthesized peptides, Lantibiotics possess biosynthetic gene clusters which contain the structural gene (lanA) as well as the other genes which are involved in lantibiotic modification (lanM, lanB, lanC, lanP), regulation (lanR, lanK), export (lanT(P)) and immunity (lanEFG). The lantibiotic mersacidin is produced by Bacillus sp. HIL Y-85,54728, which is not naturally competent. Methodology/Principal Findings: The aim of these studies was to test if the production of mersacidin could be transferred to a naturally competent Bacillus strain employing genomic DNA of the producer strain. Bacillus amyloliquefaciens FZB42 was chosen for these experiments because it already harbors the mersacidin immunity genes. After transfer of the biosynthetic part of the gene cluster by competence transformation, production of active mersacidin was obtained from a plasmid in trans. Furthermore, comparison of several DNA sequences and biochemical testing of B. amyloliquefaciens FZB42 and B. sp. HIL Y-85,54728 showed that the producer strain of mersacidin is a member of the species B. amyloliquefaciens. Conclusions/Significance: The lantibiotic mersacidin can be produced in B. amyloliquefaciens FZB42, which is closely related to the wild type producer strain of mersacidin. The new mersacidin producer strain enables us to use the full potential of th
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production of the novel two peptide lantibiotic lichenicidin by bacillus licheniformis dsm 13
PLOS ONE, 2009Co-Authors: Jasmin Dischinger, Hans-georg Sahl, Christiane Szekat, Michaele Josten, Gabriele BierbaumAbstract:Background Lantibiotics are small microbial peptide antibiotics that are characterized by the presence of the thioether amino acids lanthionine and methyllanthionine. Lantibiotics possess structural genes which encode inactive prepeptides. During maturation, the prepeptide undergoes posttranslational modifications including the introduction of rare amino acids as lanthionine and methyllanthione as well as the proteolytic removal of the leader. The structural gene (lanA) as well as the other genes which are involved in lantibiotic modification (lanM, lanB, lanC, lanP), regulation (lanR, lanK), export (lanT(P)) and immunity (lanEFG) are organized in biosynthetic gene clusters. Methodology/Principal Findings Sequence comparisons in the NCBI database showed that Bacillus licheniformis DSM 13 harbours a putative lantibiotic gene cluster which comprises two structural genes (licA1, licA2) and two modification enzymes (licM1, licM2) in addition to 10 ORFs that show sequence similarities to proteins involved in lantibiotic production. A heat labile antimicrobial activity was detected in the culture supernatant and a heat stabile activity was present in the isopropanol cell wash extract of this strain. In agar well diffusion assays both fractions exhibited slightly different activity spectra against Gram-positive bacteria. In order to demonstrate the connection between the lantibiotic gene cluster and one of the antibacterial activities, two Bacillus licheniformis DSM 13 mutant strains harbouring insertions in the structural genes of the modification enzymes licM1 and licM2 were constructed. These strains were characterized by a loss of activity in the isopropanol extract and substractive MALDI-TOF predicted masses of 3020.6 Da and 3250.6 Da for the active peptides. Conclusions/Significance In conclusion, B. licheniformis DSM 13 produces an antimicrobial substance that represents the two-peptide lantibiotic lichenicidin and that shows activity against a wide range of Gram-positive bacteria including methicillin resistant Staphylococcus aureus strains.
Leif Smith - One of the best experts on this subject based on the ideXlab platform.
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multipronged approach for engineering novel peptide analogues of existing Lantibiotics
Expert Opinion on Drug Discovery, 2015Co-Authors: Jerome Escano, Leif SmithAbstract:Introduction: Lantibiotics are a class of ribosomally and post-translationally modified peptide antibiotics that are active against a broad spectrum of Gram-positive bacteria. Great efforts have been made to promote the production of these antibiotics, so that they can one day be used in our antimicrobial arsenal to combat multidrug-resistant bacterial infections.Areas covered: This review provides a synopsis of lantibiotic research aimed at furthering our understanding of the structural limitation of Lantibiotics as well as identifying structural regions that can be modified to improve the bioactivity. In vivo, in vitro and chemical synthesis of Lantibiotics has been useful for engineering novel variants with enhanced activities. These approaches have provided novel ways to further our understanding of lantibiotic function and have advanced the objective to develop Lantibiotics for the treatment of infectious diseases.Expert opinion: Synthesis of Lantibiotics with enhanced activities will lead to the dis...
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the leader peptide of mutacin 1140 has distinct structural components compared to related class i Lantibiotics
MicrobiologyOpen, 2014Co-Authors: Jerome Escano, Byron Stauffer, Jacob Brennan, Monica Bullock, Leif SmithAbstract:Lantibiotics are ribosomally synthesized peptide antibiotics composed of an N-terminal leader peptide that promotes the core peptide's interaction with the post translational modification (PTM) enzymes. Following PTMs, mutacin 1140 is transported out of the cell and the leader peptide is cleaved to yield the antibacterial peptide. Mutacin 1140 leader peptide is structurally unique compared to other class I lantibiotic leader peptides. Herein, we further our understanding of the structural differences of mutacin 1140 leader peptide with regard to other class I leader peptides. We have determined that the length of the leader peptide is important for the biosynthesis of mutacin 1140. We have also determined that mutacin 1140 leader peptide contains a novel four amino acid motif compared to related Lantibiotics. PTM enzyme recognition of the leader peptide appears to be evolutionarily distinct from related class I Lantibiotics. Our study on mutacin 1140 leader peptide provides a basis for future studies aimed at understanding its interaction with the PTM enzymes.
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therapeutic potential of type a i Lantibiotics a group of cationic peptide antibiotics
Current Opinion in Microbiology, 2008Co-Authors: Leif Smith, Jeffrey D HillmanAbstract:Type A (I) Lantibiotics are cationic antimicrobial peptides that have a potential usefulness in treating infectious diseases. They are known to have a potent and broad spectrum of activity, an insignificant cytotoxicity, and demonstrated efficacy in animal infection models, suggesting therapeutic potential. In this review, topics pertaining to their basic structure, mode of bactericidal activity, pharmacology, and methods of manufacture are described.
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Covalent structure of mutacin 1140 and a novel method for the rapid identification of Lantibiotics.
European journal of biochemistry, 2000Co-Authors: Leif Smith, Jeffrey D Hillman, Jan Novak, James R. Rocca, Scott Mcclung, Arthur S. EdisonAbstract:The primary structure of the Streptococcus mutans lantibiotic mutacin 1140 was elucidated by NMR spectroscopy, mass spectrometry, and chemical sequencing. The structure is in agreement with other closely related Lantibiotics, such as epidermin. A novel method was developed in which mutacin 1140 was chemically modified with sodium borohydride followed by ethanethiol, allowing the differentiation of the thioether-containing residues from the dehydrated residues. This double-labeling strategy provides a simple method to reliably identify all modified lantibiotic residues with a minimal amount of material. While NMR spectroscopy is still required to obtain thioether bridging patterns and thus the complete covalent structure, the double-labeling technique, along with mass spectrometry, provides most of the information in a fraction of the time required for a complete NMR analysis. Thus, with these new techniques Lantibiotics can be rapidly characterized.
Sun H Paik - One of the best experts on this subject based on the ideXlab platform.
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identification and characterization of the structural and transporter genes for and the chemical and biological properties of sublancin 168 a novel lantibiotic produced by bacillus subtilis 168
Journal of Biological Chemistry, 1998Co-Authors: Sun H Paik, Anu Chakicherla, Norman J HansenAbstract:Abstract An antimicrobial peptide produced byBacillus subtilis 168 was isolated and characterized. It was named sublancin 168, and its behavior during Edman sequence analysis and its NMR spectrum suggested that sublancin is a dehydroalanine-containing lantibiotic. A hybridization probe based on the peptide sequence was used to clone the presublancin gene, which encoded a 56-residue polypeptide consisting of a 19-residue leader segment and a 37-residue mature segment. The mature segment contained one serine, one threonine, and five cysteine residues. Alkylation of mature sublancin showed no free sulfhydryl groups, suggesting that one sulfydryl had formed a β-methyllanthionine bridge with a dehydrobutyrine derived by posttranslational modification of threonine; with the other four cysteines forming two disulfide bridges. It is unprecedented for a lantibiotic to contain a disulfide bridge. The sublancin leader was similar to known type AII Lantibiotics, containing a double-glycine motif that is typically recognized by dual-function transporters. A protein encoded immediately downstream from the sublancin gene possessed features of a dual-function ABC transporter with a proteolytic domain and an ATP-binding domain. The antimicrobial activity spectrum of sublancin was like other Lantibiotics, inhibiting Gram-positive bacteria but not Gram-negative bacteria; and like the Lantibiotics nisin and subtilin in its ability to inhibit both bacterial spore outgrowth and vegetative growth. Sublancin is an extraordinarily stable lantibiotic, showing no degradation or inactivation after being stored in aqueous solution at room temperature for 2 years. The fact that sublancin is a natural product of B. subtilis 168, for which a great deal of genetic information is available, including the entire sequence of its genome, suggests that sublancin will be an especially good model for studying the potential of Lantibiotics as sources of novel biomaterials.
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identification and characterization of the structural and transporter genes for and the chemical and biological properties of sublancin 168 a novel lantibiotic produced by bacillus subtilis 168
Journal of Biological Chemistry, 1998Co-Authors: Sun H Paik, Anu Chakicherla, J N HansenAbstract:An antimicrobial peptide produced by Bacillus subtilis 168 was isolated and characterized. It was named sublancin 168, and its behavior during Edman sequence analysis and its NMR spectrum suggested that sublancin is a dehydroalanine-containing lantibiotic. A hybridization probe based on the peptide sequence was used to clone the presublancin gene, which encoded a 56-residue polypeptide consisting of a 19-residue leader segment and a 37-residue mature segment. The mature segment contained one serine, one threonine, and five cysteine residues. Alkylation of mature sublancin showed no free sulfhydryl groups, suggesting that one sulfydryl had formed a beta-methyllanthionine bridge with a dehydrobutyrine derived by posttranslational modification of threonine; with the other four cysteines forming two disulfide bridges. It is unprecedented for a lantibiotic to contain a disulfide bridge. The sublancin leader was similar to known type AII Lantibiotics, containing a double-glycine motif that is typically recognized by dual-function transporters. A protein encoded immediately downstream from the sublancin gene possessed features of a dual-function ABC transporter with a proteolytic domain and an ATP-binding domain. The antimicrobial activity spectrum of sublancin was like other Lantibiotics, inhibiting Gram-positive bacteria but not Gram-negative bacteria; and like the Lantibiotics nisin and subtilin in its ability to inhibit both bacterial spore outgrowth and vegetative growth. Sublancin is an extraordinarily stable lantibiotic, showing no degradation or inactivation after being stored in aqueous solution at room temperature for 2 years. The fact that sublancin is a natural product of B. subtilis 168, for which a great deal of genetic information is available, including the entire sequence of its genome, suggests that sublancin will be an especially good model for studying the potential of Lantibiotics as sources of novel biomaterials.
Oscar P. Kuipers - One of the best experts on this subject based on the ideXlab platform.
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design and expression of specific hybrid Lantibiotics active against pathogenic clostridium spp
Frontiers in Microbiology, 2019Co-Authors: Ruben Cebrian, Alicia Maciavalero, Afif Pranaya Jati, Oscar P. KuipersAbstract:Clostridium difficile has been reported as the most common cause of nosocomial diarrhea (antibiotic-associated diarrhea), resulting in significant morbidity and mortality in hospitalized patients. The resistance of the clostridial spores to antibiotics and their side effects on the gut microbiota are two factors related to the emergence of infection and its relapses. Lantibiotics provide an innovative alternative for cell growth inhibition due to their dual mechanism of action (membrane pore-forming and cell wall synthesis inhibition) and low resistance rate. Based on the fact that bacteriocins are usually active against bacteria closely related to the producer strains, a new dual approach combining genome mining and synthetic biology was performed, by designing new Lantibiotics with high activity and specificity toward Clostridium. We first attempted the heterologous expression of putative Lantibiotics identified following Clostridium genome mining. Subsequently, we designed new hybrid Lantibiotics combining the start or end of the putative clostridial peptides and the start or end parts of nisin. The designed peptides were cloned and expressed using the nisin biosynthetic machinery in Lactococcus lactis. From the 20 initial peptides, only 1 fulfilled the requirements established in this work to be considered as a good candidate: high heterologous production level and high specificity/activity against clostridial species. The high specificity and activity observed for the peptide AMV10 makes it an interesting candidate as an alternative to traditional antibiotics in the treatment of C. difficile infections, avoiding side effects and protecting the normal gut microbiota.
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evaluating the feasibility of Lantibiotics as an alternative therapy against bacterial infections in humans
Expert Opinion on Drug Metabolism & Toxicology, 2011Co-Authors: Auke J Van Heel, Manuel Montalbanlopez, Oscar P. KuipersAbstract:Since the commercialization and ubiquitous use of antibiotics in the 20th century, there has been a steady increase in the number of reports on resistant bacteria. In recent years, this situation has become even more dramatic. The relatively slow development of new drugs, especially those with novel modes of action on target bacteria, is not paired with the rapid rate of resistance appearance. Lantibiotics form a group of antimicrobial peptides of bacterial origin with a dual mechanism of action not shared by other therapeutic compounds in use. They have a high potency to inhibit diverse (multidrug resistant) bacteria, combined with a low tendency to generate resistance. These properties make Lantibiotics attractive candidates for clinical applications. This paper discusses some of the most recent results obtained in lantibiotic clinical application, paying special attention to the pharmacokinetic and pharmacodynamic properties they display. The objective of this paper is to give insight into the actual clinical applicability of Lantibiotics and to point to the unexplored aspects that should be addressed in future research. The authors feel that Lantibiotics could increase the number of second line antibiotics for systemic use in the future; however, further research is still needed before this is possible.
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an alternative bactericidal mechanism of action for lantibiotic peptides that target lipid ii
Science, 2006Co-Authors: Hester E Hasper, Naomi E Kramer, James Leif Smith, Jeffrey D Hillman, Cherian Zachariah, Oscar P. Kuipers, Eefjan BreukinkAbstract:Lantibiotics are polycyclic peptides containing unusual amino acids, which have binding specificity for bacterial cells, targeting the bacterial cell wall component lipid II to form pores and thereby lyse the cells. Yet several members of these lipid II–targeted Lantibiotics are too short to be able to span the lipid bilayer and cannot form pores, but somehow they maintain their antibacterial efficacy. We describe an alternative mechanism by which members of the lantibiotic family kill Gram-positive bacteria by removing lipid II from the cell division site (or septum) and thus block cell wall synthesis.
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nist the transporter of the lantibiotic nisin can transport fully modified dehydrated and unmodified prenisin and fusions of the leader peptide with non lantibiotic peptides
Journal of Biological Chemistry, 2004Co-Authors: Anneke Kuipers, Esther De Boef, Susan Fekken, Rick Rink, Kees Leenhouts, Leon Kluskens, Oscar P. Kuipers, Arnold J. M. Driessen, Gert N. MollAbstract:Lantibiotics are lanthionine-containing peptide antibiotics. Nisin, encoded by nisA, is a pentacyclic lantibiotic produced by some Lactococcus lactis strains. Its thioether rings are posttranslationally introduced by a membrane-bound enzyme complex. This complex is composed of three enzymes: NisB, which dehydrates serines and threonines; NisC, which couples these dehydrated residues to cysteines, thus forming thioether rings; and the transporter NisT. We followed the activity of various combinations of the nisin enzymes by measuring export of secreted peptides using antibodies against the leader peptide and mass spectroscopy for detection. L. lactis expressing the nisABTC genes efficiently produced fully posttranslationally modified prenisin. Strikingly, L. lactis expressing the nisBT genes could produce dehydrated prenisin without thioether rings and a dehydrated form of a non-lantibiotic peptide. In the absence of the biosynthetic NisBC enzymes, the NisT transporter was capable of excreting unmodified prenisin and fusions of the leader peptide with non-lantibiotic peptides. Our data show that NisT specifies a broad spectrum (poly)peptide transporter that can function either in conjunction with or independently from the biosynthetic genes. NisT secretes both unmodified and partially or fully posttranslationally modified forms of prenisin and non-lantibiotic peptides. These results open the way for efficient production of a wide range of peptides with increased stability or novel bioactivities.
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Protein engineering of Lantibiotics
Antonie van Leeuwenhoek, 1996Co-Authors: Oscar P. Kuipers, Gabriele Bierbaum, Birgit Ottenwälder, Helen M. Dodd, Nicky Horn, Jörg Metzger, Thomas Kupke, Volker Gnau, Roger Bongers, Patrick BogaardAbstract:Whereas protein engineering of enzymes and structural proteins nowadays is an established research tool for studying structure-function relationships of polypeptides and for improving their properties, the engineering of posttranslationally modified peptides, such as the Lantibiotics, is just coming of age. The engineering of Lantibiotics is less straightforward than that of unmodified proteins, since expression systems should be developed not only for the structural genes but also for the genes encoding the biosynthetic enzymes, immunity protein and regulatory proteins. Moreover, correct posttranslational modification of specific residues could in many cases be a prerequisite for production and secretion of the active lantibiotic, which limits the number of successful mutations one can apply. This paper describes the development of expression systems for the structural lantibiotic genes for nisin A, nisin Z, gallidermin, epidermin and Pep5, and gives examples of recently produced site-directed mutants of these Lantibiotics. Characterization of the mutants yielded valuable information on biosynthetic requirements for production. Moreover, regions in the Lantibiotics were identified that are of crucial importance for antimicrobial activity. Eventually, this knowledge will lead to the rational design of Lantibiotics optimally suited for fighting specific undesirable microorganisms. The mutants are of additional value for studies directed towards the elucidation of the mode of action of Lantibiotics.
Imke Wiedemann - One of the best experts on this subject based on the ideXlab platform.
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Lipid II-Based Antimicrobial Activity of the Lantibiotic Plantaricin C
Applied and Environmental Microbiology, 2006Co-Authors: Imke Wiedemann, Tim Böttiger, Raquel Regina Bonelli, Hans-georg Sahl, Tanja Schneider, Beatriz MartínezAbstract:We analyzed the mode of action of the lantibiotic plantaricin C (PlnC), produced by Lactobacillus plantarum LL441. Compared to the well-characterized type A lantibiotic nisin and type B lantibiotic mersacidin, which are both able to interact with the cell wall precursor lipid II, PlnC displays structural features of both prototypes. In this regard, we found that lipid II plays a key role in the antimicrobial activity of PlnC besides that of pore formation. The pore forming activity of PlnC in whole cells was prevented by shielding lipid II on the cell surface. However, in contrast to nisin, PlnC was not able to permeabilize Lactococcus lactis cells or to form pores in 1,2-dioleoyl-sn-glycero-3-phosphocholine liposomes supplemented with 0.1 mol% purified lipid II. This emphasized the different requirements of these Lantibiotics for pore formation. Using cell wall synthesis assays, we identified PlnC as a potent inhibitor of (i) lipid II synthesis and (ii) the FemX reaction, i.e., the addition of the first Gly to the pentapeptide side chain of lipid II. As revealed by thin-layer chromatography, both reactions were clearly blocked by the formation of a PlnC-lipid I and/or PlnC-lipid II complex. On the basis of the in vivo and in vitro activities of PlnC shown in this study and the structural lipid II binding motifs described for other Lantibiotics, the specific interaction of PlnC with lipid II is discussed.
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Insights into In Vivo Activities of Lantibiotics from Gallidermin and Epidermin Mode-of-Action Studies
Antimicrobial agents and chemotherapy, 2006Co-Authors: Raquel Regina Bonelli, Hans-georg Sahl, Tanja Schneider, Imke WiedemannAbstract:The activity of lanthionine-containing peptide antibiotics (Lantibiotics) is based on different killing mechanisms which may be combined in one molecule. The prototype lantibiotic nisin inhibits peptidoglycan synthesis and forms pores through specific interaction with the cell wall precursor lipid II. Gallidermin and epidermin possess the same putative lipid II binding motif as nisin; however, both peptides are considerably shorter (22 amino acids, compared to 34 in nisin). We demonstrate that in model membranes, lipid II-mediated pore formation by gallidermin depends on membrane thickness. With intact cells, pore formation was less pronounced than for nisin and occurred only in some strains. In Lactococcus lactis subsp. cremoris HP, gallidermin was not able to release K+, and a mutant peptide, [A12L]gallidermin, in which the ability to form pores was disrupted, was as potent as wild-type gallidermin, indicating that pore formation does not contribute to killing. In contrast, nisin rapidly formed pores in the L. lactis strain; however, it was approximately 10-fold less effective in killing. The superior activity of gallidermin in a cell wall biosynthesis assay may help to explain this high potency. Generally, it appears that the multiple activities of Lantibiotics combine differently for individual target strains.
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Combination of antibiotic mechanisms in Lantibiotics.
Farmaco (Societa chimica italiana : 1989), 2002Co-Authors: Anja Hoffmann, Imke Wiedemann, Ulrike Pag, Hans-georg SahlAbstract:Recent studies on the mode of action have revealed exciting features of multiple activities of nisin and related Lantibiotics making these peptides interesting model systems for the design of new antibiotics (Molec. Microbiol. 30 (1998) 317; Science 286 (1999) 2361; J. Biol. Chem. 276 (2001) 1772.). In contrast to other groups of antibiotic peptides, the Lantibiotics display a substantial degree of specificity for particular components of bacterial membranes. Mersacidin and actagardine were shown to bind with high affinity to the lipid coupled peptidoglycan precursor, the so-called lipid II, which prevents the polymerisation of the cell wall monomers into a functional murein sacculus. The Lantibiotics nisin and epidermin also bind tightly to this cell wall precursor; however, for these Lantibiotics the binding of lipid II has two consequences. Like with mersacidin blocking of lipid II inhibits peptidoglycan biosynthesis; in addition, lipid II is used as a specific docking molecule for the formation of pores. This combination of lethal effects explains the potency of these peptides, which are active in nanomolar concentration. Other type-A Lantibiotics are believed to also use docking molecules for pore formation, although identification of such membrane components has not yet been achieved.
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posttranslationally modified bacteriocins the Lantibiotics
Biopolymers, 2000Co-Authors: André Guder, Imke Wiedemann, Hans-georg SahlAbstract:Lantibiotics are a subgroup of bacteriocins that are characterized by the presence of the unusual thioether amino acids lanthionine and 3-methyllanthionine generated through posttranslational modification. The biosynthesis of Lantibiotics follows a defined pathway comprising modifications of the prepeptide, proteolytic activation, and export. The genes encoding the biosynthesis apparatus and the lantibiotic prepeptide are organized in clusters, which also include information for proteins involved in regulation and producer self-protection. The elongated cationic Lantibiotics primarily act through the formation of pores and recent progress with nisin and epidermin has shown that specific docking molecules such as lipid II play an essential role in this mechanism. Mersacidin and actagardine inhibit cell wall biosynthesis by complexing the precursor lipid II, whereas the cinnamycin-like peptides bind to phosphoethanolamine thus inhibiting phospholipase A2. © 2000 John Wiley & Sons, Inc. Biopoly 55: 62–73, 2000
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posttranslationally modified bacteriocins the Lantibiotics
Biopolymers, 2000Co-Authors: André Guder, Imke Wiedemann, Hans-georg SahlAbstract:Lantibiotics are a subgroup of bacteriocins that are characterized by the presence of the unusual thioether amino acids lanthionine and 3-methyllanthionine generated through posttranslational modification. The biosynthesis of Lantibiotics follows a defined pathway comprising modifications of the prepeptide, proteolytic activation, and export. The genes encoding the biosynthesis apparatus and the lantibiotic prepeptide are organized in clusters, which also include information for proteins involved in regulation and producer self-protection. The elongated cationic Lantibiotics primarily act through the formation of pores and recent progress with nisin and epidermin has shown that specific docking molecules such as lipid II play an essential role in this mechanism. Mersacidin and actagardine inhibit cell wall biosynthesis by complexing the precursor lipid II, whereas the cinnamycin-like peptides bind to phosphoethanolamine thus inhibiting phospholipase A2.
