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Lanthipeptide

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https://www.readbyqxmd.com/read/29615987/mutacin-1140-lantibiotic-variants-are-efficacious-against-clostridium-difficile-infection
#1
Johan A Kers, Robert E Sharp, Anthony W Defusco, Jae H Park, Jin Xu, Mark E Pulse, William J Weiss, Martin Handfield
Lantibiotics offer an untapped pipeline for the development of novel antibiotics to treat serious Gram-positive (+) infections including Clostridium difficile . Mutacin 1140 (MU1140) is a lantibiotic produced by Streptococcus mutans and acts via a novel mechanism of action, which may limit the development of resistance. This study sought to identify a lead compound for the treatment of C. difficile associated diarrhea (CDAD). Compounds were selected from a saturation mutagenesis library of 418 single amino acid variants of MU1140...
2018: Frontiers in Microbiology
https://www.readbyqxmd.com/read/29507389/a-lanthipeptide-library-used-to-identify-a-protein-protein-interaction-inhibitor
#2
Xiao Yang, Katherine R Lennard, Chang He, Mark C Walker, Andrew T Ball, Cyrielle Doigneaux, Ali Tavassoli, Wilfred A van der Donk
In this article we describe the production and screening of a genetically encoded library of 106 lanthipeptides in Escherichia coli using the substrate-tolerant lanthipeptide synthetase ProcM. This plasmid-encoded library was combined with a bacterial reverse two-hybrid system for the interaction of the HIV p6 protein with the UEV domain of the human TSG101 protein, which is a critical protein-protein interaction for HIV budding from infected cells. Using this approach, we identified an inhibitor of this interaction from the lanthipeptide library, whose activity was verified in vitro and in cell-based virus-like particle-budding assays...
March 5, 2018: Nature Chemical Biology
https://www.readbyqxmd.com/read/29291350/accessing-chemical-diversity-from-the-uncultivated-symbionts-of-small-marine-animals
#3
Thomas E Smith, Christopher D Pond, Elizabeth Pierce, Zachary P Harmer, Jason Kwan, Malcolm M Zachariah, Mary Kay Harper, Thomas P Wyche, Teatulohi K Matainaho, Tim S Bugni, Louis R Barrows, Chris M Ireland, Eric W Schmidt
Chemistry drives many biological interactions between the microbiota and host animals, yet it is often challenging to identify the chemicals involved. This poses a problem, as such small molecules are excellent sources of potential pharmaceuticals, pretested by nature for animal compatibility. We discovered anti-HIV compounds from small, marine tunicates from the Eastern Fields of Papua New Guinea. Tunicates are a reservoir for new bioactive chemicals, yet their small size often impedes identification or even detection of the chemicals within...
February 2018: Nature Chemical Biology
https://www.readbyqxmd.com/read/29195488/improving-the-attrition-rate-of-lanthipeptide-discovery-for-commercial-applications
#4
Mengxin Geng, Leif Smith
Lanthipeptides are a class of ribosomally synthesized and post-translationally modified peptides. Lanthipeptides with antimicrobial activity are referred to as lantibiotics. Lantibiotics are generally active against Gram-positive bacteria. However, some modifications have expanded their activity toward Gram-negative bacteria. Furthermore, additional functions aside from antibacterial activities have been reported for lanthipeptides. Areas covered: This review provides a synopsis of current anthipeptide research for potential therapeutics...
February 2018: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/29186395/bacillus-amyloliquefaciens-ssp-plantarum-f11-isolated-from-algerian-salty-lake-as-a-source-of-biosurfactants-and-bioactive-lipopeptides
#5
Mohamed Seghir Daas, Jeella Z Acedo, Albert Remus R Rosana, Fabini D Orata, Béla Reiz, Jing Zheng, Farida Nateche, Rebecca J Case, Salima Kebbouche-Gana, John C Vederas
In this study, we identified a new Bacillus strain isolated from an Algerian salty lake that produces metabolites that are active against Gram-positive and Gram-negative bacteria, as well as fungal pathogens. The draft genome sequence of the strain is presented herein. Genome sequence analysis identified the strain to be B. amyloliquefaciens subspecies plantarum F11, and showed that the strain carries the gene clusters for the production of a number of bioactive and surface-active compounds. These include the lipopeptides surfactin and fengycin, antibacterial polyketides macrolactin and bacillaene, and a putative novel lanthipeptide, among others...
January 1, 2018: FEMS Microbiology Letters
https://www.readbyqxmd.com/read/29158402/structural-insights-into-enzymatic-4-2-aza-cycloaddition-in-thiopeptide-antibiotic-biosynthesis
#6
Dillon P Cogan, Graham A Hudson, Zhengan Zhang, Taras V Pogorelov, Wilfred A van der Donk, Douglas A Mitchell, Satish K Nair
The [4+2] cycloaddition reaction is an enabling transformation in modern synthetic organic chemistry, but there are only limited examples of dedicated natural enzymes that can catalyze this transformation. Thiopeptides (or more formally thiazolyl peptides) are a class of thiazole-containing, highly modified, macrocyclic secondary metabolites made from ribosomally synthesized precursor peptides. The characteristic feature of these natural products is a six-membered nitrogenous heterocycle that is assembled via a formal [4+2] cycloaddition between two dehydroalanine (Dha) residues...
December 5, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29138389/phage-display-and-selection-of-lanthipeptides-on-the-carboxy-terminus-of-the-gene-3-minor-coat-protein
#7
Johannes H Urban, Markus A Moosmeier, Tobias Aumüller, Marcus Thein, Tjibbe Bosma, Rick Rink, Katharina Groth, Moritz Zulley, Katja Siegers, Kathrin Tissot, Gert N Moll, Josef Prassler
Ribosomally synthesized and post-translationally modified peptides (RiPPs) are an emerging class of natural products with drug-like properties. To fully exploit the potential of RiPPs as peptide drug candidates, tools for their systematic engineering are required. Here we report the engineering of lanthipeptides, a subclass of RiPPs characterized by multiple thioether cycles that are enzymatically introduced in a regio- and stereospecific manner, by phage display. This was achieved by heterologous co-expression of linear lanthipeptide precursors fused to the widely neglected C-terminus of the bacteriophage M13 minor coat protein pIII, rather than the conventionally used N-terminus, along with the modifying enzymes from distantly related bacteria...
November 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/28809560/recombinant-macrocyclic-lanthipeptides-incorporating-non-canonical-amino-acids
#8
Claudio Zambaldo, Xiaozhou Luo, Angad P Mehta, Peter G Schultz
Nisin is a complex lanthipeptide that has broad spectrum antibacterial activity. In efforts to broaden the structural diversity of this ribosomally synthesized lantibiotic, we now report the recombinant expression of Nisin variants that incorporate noncanonical amino acids (ncAAs) at discrete positions. This is achieved by expressing the nisA structural gene, cyclase (nisC) and dehydratase (nisB), together with an orthogonal nonsense suppressor tRNA/aminoacyl-tRNA synthetase pair in Escherichia coli. A number of ncAAs with novel chemical reactivity were genetically incorporated into NisA, including an α-chloroacetamide-containing ncAA that allowed for the expression of Nisin variants with novel macrocyclic topologies...
August 15, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28691075/chimeric-leader-peptides-for-the-generation-of-non-natural-hybrid-ripp-products
#9
Brandon J Burkhart, Nidhi Kakkar, Graham A Hudson, Wilfred A van der Donk, Douglas A Mitchell
Combining biosynthetic enzymes from multiple pathways is an attractive approach for producing molecules with desired structural features; however, progress has been hampered by the incompatibility of enzymes from unrelated pathways and intolerance toward alternative substrates. Ribosomally synthesized and posttranslationally modified peptides (RiPPs) are a diverse natural product class that employs a biosynthetic logic that is highly amenable to engineering new compounds. RiPP biosynthetic proteins modify their substrates by binding to a motif typically located in the N-terminal leader region of the precursor peptide...
June 28, 2017: ACS Central Science
https://www.readbyqxmd.com/read/28675292/substrate-specificity-of-the-secreted-nisin-leader-peptidase-nisp
#10
Marcel Lagedroste, Sander H J Smits, Lutz Schmitt
Nisin (NisA) is an antimicrobial peptide produced by Lactococcus lactis and belongs to the class of lanthipeptides, more specifically to the class of lantibiotics. They are ribosomally synthesized as a precursor peptide and are comprised of an N-terminal leader peptide and a C-terminal core peptide. The core peptide is post-translationally modified and contains dehydrated amino acids in addition to five (methyl)-lanthionine rings, which are crucial for its activity. The leader peptide serves as a signal sequence and ensures that NisA remains inactive but secretion-competent within the cell...
August 1, 2017: Biochemistry
https://www.readbyqxmd.com/read/28667105/bacteriocins-of-non-aureus-staphylococci-isolated-from-bovine-milk
#11
Domonique A Carson, Herman W Barkema, Sohail Naushad, Jeroen De Buck
Non- aureus staphylococci (NAS), the bacteria most commonly isolated from the bovine udder, potentially protect the udder against infection by major mastitis pathogens due to bacteriocin production. In this study, we determined the inhibitory capability of 441 bovine NAS isolates (comprising 26 species) against bovine Staphylococcus aureus Furthermore, inhibiting isolates were tested against a human methicillin-resistant S. aureus (MRSA) isolate using a cross-streaking method. We determined the presence of bacteriocin clusters in NAS whole genomes using genome mining tools, BLAST, and comparison of genomes of closely related inhibiting and noninhibiting isolates and determined the genetic organization of any identified bacteriocin biosynthetic gene clusters...
September 1, 2017: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/28650175/bioactive-peptide-natural-products-as-lead-structures-for-medicinal-use
#12
Tam Dang, Roderich D Süssmuth
The need for new drugs for the treatment of various diseases is enormous. From the previous century until the present, numerous peptide and peptide-derived natural products have been isolated from bacteria and fungi. Hence, microorganisms play a pivotal role as sources for novel drugs with an emphasis on anti-infective agents. Various disciplines from biology, chemistry, and medicine are involved in early stages of the search for peptide natural products including taxonomy, microbiology, bioanalytics, bioinformatics, and medicinal chemistry...
June 26, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28630351/evolutionary-radiation-of-lanthipeptides-in-marine-cyanobacteria
#13
Andres Cubillos-Ruiz, Jessie W Berta-Thompson, Jamie W Becker, Wilfred A van der Donk, Sallie W Chisholm
Lanthipeptides are ribosomally derived peptide secondary metabolites that undergo extensive posttranslational modification. Prochlorosins are a group of lanthipeptides produced by certain strains of the ubiquitous marine picocyanobacteria Prochlorococcus and Synechococcus Unlike other lanthipeptide-producing bacteria, picocyanobacteria use an unprecedented mechanism of substrate promiscuity for the production of numerous and diverse lanthipeptides using a single lanthionine synthetase. Through a cross-scale analysis of prochlorosin biosynthesis genes-from genomes to oceanic populations-we show that marine picocyanobacteria have the collective capacity to encode thousands of different cyclic peptides, few of which would display similar ring topologies...
July 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28499008/rippminer-a-bioinformatics-resource-for-deciphering-chemical-structures-of-ripps-based-on-prediction-of-cleavage-and-cross-links
#14
Priyesh Agrawal, Shradha Khater, Money Gupta, Neetu Sain, Debasisa Mohanty
Ribosomally synthesized and post-translationally modified peptides (RiPPs) constitute a rapidly growing class of natural products with diverse structures and bioactivities. We have developed RiPPMiner, a novel bioinformatics resource for deciphering chemical structures of RiPPs by genome mining. RiPPMiner derives its predictive power from machine learning based classifiers, trained using a well curated database of more than 500 experimentally characterized RiPPs. RiPPMiner uses Support Vector Machine to distinguish RiPP precursors from other small proteins and classify the precursors into 12 sub-classes of RiPPs...
May 12, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28155176/erratum-to-pharmacological-and-pharmacokinetic-properties-of-lanthipeptides-undergoing-clinical-studies
#15
Elvis Legala Ongey, Hüseyin Yassi, Stephan Pflugmacher, Peter Neubauer
No abstract text is available yet for this article.
February 2, 2017: Biotechnology Letters
https://www.readbyqxmd.com/read/28135077/mechanistic-understanding-of-lanthipeptide-biosynthetic-enzymes
#16
REVIEW
Lindsay M Repka, Jonathan R Chekan, Satish K Nair, Wilfred A van der Donk
Lanthipeptides are ribosomally synthesized and post-translationally modified peptides (RiPPs) that display a wide variety of biological activities, from antimicrobial to antiallodynic. Lanthipeptides that display antimicrobial activity are called lantibiotics. The post-translational modification reactions of lanthipeptides include dehydration of Ser and Thr residues to dehydroalanine and dehydrobutyrine, a transformation that is carried out in three unique ways in different classes of lanthipeptides. In a cyclization process, Cys residues then attack the dehydrated residues to generate the lanthionine and methyllanthionine thioether cross-linked amino acids from which lanthipeptides derive their name...
April 26, 2017: Chemical Reviews
https://www.readbyqxmd.com/read/28106097/lancl-proteins-are-not-involved-in-lanthionine-synthesis-in-mammals
#17
Chang He, Min Zeng, Debapriya Dutta, Tong Hee Koh, Jie Chen, Wilfred A van der Donk
LanC-like (LanCL) proteins are mammalian homologs of bacterial LanC enzymes, which catalyze the addition of the thiol of Cys to dehydrated Ser residues during the biosynthesis of lanthipeptides, a class of natural products formed by post-translational modification of precursor peptides. The functions of LanCL proteins are currently unclear. A recent proposal suggested that LanCL1 catalyzes the addition of the Cys of glutathione to protein- or peptide-bound dehydroalanine (Dha) to form lanthionine, analogous to the reaction catalyzed by LanC in bacteria...
January 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28044226/pharmacological-and-pharmacokinetic-properties-of-lanthipeptides-undergoing-clinical-studies
#18
REVIEW
Elvis Legala Ongey, Hüseyin Yassi, Stephan Pflugmacher, Peter Neubauer
The intrinsic qualities of lanthipeptides for their use as therapeutic drugs present several challenges because of their properties, which include stability, solubility and bioavailability, which, under physiological conditions, are very low. Researches have encouraged clinical evaluation of a few compounds, such as mutacin 1140, microbisporicin, actagardine and duramycin, with pharmacokinetic profiles showing rapid distribution and elimination rates, good bioavailability and fecal excretion, as well as high protein binding...
April 2017: Biotechnology Letters
https://www.readbyqxmd.com/read/27934350/synthesis-and-bioactivity-of-diastereomers-of-the-virulence-lanthipeptide-cytolysin
#19
Subha Mukherjee, Liujie Huo, Gabrielle N Thibodeaux, Wilfred A van der Donk
Cytolysin, a two-component lanthipeptide comprising cytolysin S (CylLS ″) and cytolysin L (CylLL ″), is the only family member to exhibit lytic activity against mammalian cells in addition to synergistic antimicrobial activity. A subset of the thioether cross-links of CylLS ″ and CylLL ″ have ll stereochemistry instead of the canonical dl stereochemistry in all previously characterized lanthipeptides. The synthesis of a CylLS ″ variant with dl stereochemistry is reported. Its antimicrobial activity was found to be decreased, but not its lytic activity against red blood cells...
December 2, 2016: Organic Letters
https://www.readbyqxmd.com/read/27924934/one-pot-synthesis-of-class-ii-lanthipeptide-bovicin-hj50-via-an-engineered-lanthipeptide-synthetase
#20
Jian Wang, Xiaoxuan Ge, Li Zhang, Kunling Teng, Jin Zhong
Lanthipeptides are a large class of bacteria-produced, ribosomally-synthesized and post-translationally modified peptides. They are recognized as peptide antibiotics because most of them exhibit potent antimicrobial activities against Gram-positive bacteria especially those that are phylogenetically related to producers. Maturation of class II lanthipeptide like bovicin HJ50 undergoes precursor modification by LanM and a subsequent leader peptide cleavage by LanT. Herein, via co-expression of precursor gene bovA, modification gene bovM and transporter gene bovT in Escherichia coli C43 (DE3), bioactive bovicin HJ50 was successfully produced and secreted...
December 7, 2016: Scientific Reports
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