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Mengxin Geng, Leif Smith
Mutacin 1140 belongs to the epidermin family of type AI lantibiotics. This family has a broad spectrum of activity against Gram-positive bacteria. The binding of mutacin 1140 to lipid II leads to the inhibition of cell wall synthesis. Pharmacokinetic experiments on type AI lantibiotics are generally discouraging for clinical applications due to their short half-life. The unprotected dehydrated and protease susceptible residues outside of the lanthionine rings may play a role in their short half-life in physiological settings...
May 18, 2018: Applied and Environmental Microbiology
Patrick Ebner, Sebastian Reichert, Arif Luqman, Bernhard Krismer, Peter Popella, Friedrich Götz
Lantibiotics are antimicrobial peptides that contain non-proteinogenic amino acids lanthionine and 3-methyllanthionine and are produced by Gram-positive bacteria. Here we addressed the pros and cons of lantibiotic production for its producing strains. Two staphylococcal strains, S. gallinarum Tü3928 and S. epidermidis Tü3298 producing gallidermin and epidermin respectively were selected. In each of these parental strains, the structural genes gdmA and epiA were deleted; all the other biosynthetic genes including the immunity genes were left intact...
May 10, 2018: Scientific Reports
Thibaut Denoel, Christian Lemaire, André Luxen
Lanthionine (Lan), a non-proteinogenic natural amino acid, is an essential component of peptidoglycan found in the cell wall of Fusobacterium species. Lan and β-methyllanthionine are also key constituents in lantibiotics, a prevalent class of peptide antibiotics. The development of those new antibacterial drugs with enhanced properties is the focus of recent research. Since multiple isomers of Lan are possible, a regio- and diastereoselective synthesis is challenging. This comprehensive review summarizes the known chemical syntheses of lanthionine from various precursors (e...
May 1, 2018: Chemistry: a European Journal
Harsh Mathur, Des Field, Mary C Rea, Paul D Cotter, Colin Hill, R Paul Ross
Biofilms are sessile communities of bacteria typically embedded in an extracellular polymeric matrix. Bacterial cells embedded in biofilms are inherently recalcitrant to antimicrobials, compared to cells existing in a planktonic state, and are notoriously difficult to eradicate once formed. Avenues to tackle biofilms thus far have largely focussed on attempting to disrupt the initial stages of biofilm formation, including adhesion and maturation of the biofilm. Such an approach is advantageous as the concentrations required to inhibit formation of biofilms are generally much lower than removing a fully established biofilm...
2018: NPJ Biofilms and Microbiomes
Maike Bartholomae, Tobias Baumann, Jessica H Nickling, David Peterhoff, Ralf Wagner, Nediljko Budisa, Oscar P Kuipers
The incorporation of non-canonical amino acids (ncAAs) into ribosomally synthesized and post-translationally modified peptides, e.g., nisin from the Gram-positive bacterium Lactococcus lactis , bears great potential to expand the chemical space of various antimicrobials. The ncAA N ε -Boc-L-lysine (BocK) was chosen for incorporation into nisin using the archaeal pyrrolysyl-tRNA synthetase-tRNAPyl pair to establish orthogonal translation in L. lactis for read-through of in-frame amber stop codons. In parallel, recombinant nisin production and orthogonal translation were combined in Escherichia coli cells...
2018: Frontiers in Microbiology
Qian Li, Manuel Montalban-Lopez, Oscar P Kuipers
Lantibiotics are ribosomally synthesized and posttranslationally modified antimicrobial compounds containing lanthionine and methyl-lanthionine residues. Nisin, one of the most extensively studied and used lantibiotics, has been shown to display a very potent activity against Gram-positive bacteria and stable resistance is rarely observed. By binding to lipid II and forming pores in the membrane, nisin can cause efflux of cellular constituents and inhibit cell wall biosynthesis. However, the activity of nisin against Gram-negative bacteria is much lower than that against Gram-positive bacteria, mainly because lipid II is located at the inner-membrane and the rather impermeable outer-membrane in Gram-negative bacteria prevents nisin from reaching lipid II...
April 6, 2018: Applied and Environmental Microbiology
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
Thea Magrone, Matteo Antonio Russo, Emilio Jirillo
Antimicrobial peptides (AMPs) are phylogenetically ancient substances released by living organisms for self protection against a broad variety of microbes. Moreover, AMPs are endowed with immune modulatory activities, linking innate and adaptive immunity together. Lantibiotics are AMPs of bacterial origin currently investigated for the generation of a new class of anti-infective compounds, owing to the phenomenon of antibiotic resistance against a broad variety of bacteria. Also, plants and marine AMPs are screened as novel drugs against human pathogens...
April 3, 2018: Current Pharmaceutical Design
Torbjörn Bengtsson, Johanna Lönn, Hazem Khalaf, Eleonor Palm
Antimicrobial resistance needs to be tackled from new angles, and antimicrobial peptides could be future candidates for combating bacterial infections. This study aims to investigate in vitro the bactericidal effects of the lantibiotic gallidermin on Staphylococcus epidermidis and Staphylococcus aureus, possible cytotoxic effects and its impact on host-microbe interactions. Minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of gallidermin were determined, and cytotoxicity and proinflammatory effects of gallidermin on fibroblasts, red blood cells (RBCs) and in whole blood were investigated...
March 13, 2018: MicrobiologyOpen
Ashwini B Dolle, Narasimhappagari Jagadeesh, Suman Bhaumik, Sunita Prakash, Himansu S Biswal, Konkallu Hanumae Gowd
RATIONALE: The modes of cleavage of lanthionine/methyllanthionine bridges under electron transfer dissociation (ETD) were investigated using synthetic and natural lantipeptides. Knowledge of the mass spectrometric fragmentation of lanthionine/methyllanthionine bridges may assist in the development of analytical methods for the rapid discovery of new lantibiotics. The present study strengthens the advantage of ETD in the characterization of posttranslational modifications of peptides and proteins...
June 15, 2018: Rapid Communications in Mass Spectrometry: RCM
Sahar Hasim, David P Allison, Berlin Mendez, Abigail T Farmer, Dale A Pelletier, Scott T Retterer, Shawn R Campagna, Todd B Reynolds, Mitchel J Doktycz
The use of naturally occurring antimicrobial peptides provides a promising route to selectively target pathogenic agents and to shape microbiome structure. Lantibiotics, such as duramycin, are one class of bacterially produced peptidic natural products that can selectively inhibit the growth of other bacteria. However, despite longstanding characterization efforts, the microbial selectivity and mode of action of duramycin are still obscure. We describe here a suite of biological, chemical, and physical characterizations that shed new light on the selective and mechanistic aspects of duramycin activity...
2018: Frontiers in Microbiology
Manuel Montalbán-López, Jingjing Deng, Auke J van Heel, Oscar P Kuipers
Lantibiotics are ribosomally produced and posttranslationally modified peptides containing several lanthionine residues. They exhibit substantial antimicrobial activity against Gram-positive bacteria, including relevant pathogens. The production of the model lantibiotic nisin minimally requires the expression of the modification and export machinery. The last step during nisin maturation is the cleavage of the leader peptide. This liberates the active compound and is catalyzed by the cell wall-anchored protease NisP...
2018: Frontiers in Microbiology
Yasushi Ogasawara, Tohru Dairi
D-Amino acid residues have been identified in peptides from a variety of eukaryotes and prokaryotes. In microorganisms, UDP- N -acetylmuramic acid pentapeptide (UDP-MurNAc-L-Ala-D-Glu-meso-diaminopimelate-D-Ala-D-Ala), a unit of peptidoglycan, is a representative. During its biosynthesis, D-Ala and D-Glu are generally supplied by racemases from the corresponding isomers. However, we recently identified a unique unidirectional L-Glu epimerase catalyzing the epimerization of the terminal L-Glu of UDP-MurNAc-L-Ala-L-Glu...
2018: Frontiers in Microbiology
Nidhi Kakkar, Jessica G Perez, Wenshe R Liu, Michael C Jewett, Wilfred A van der Donk
Lantibiotics are ribosomally synthesized and post-translationally modified peptide natural products that contain thioether cross-links formed by lanthionine and methyllanthionine residues. They exert potent antimicrobial activity against Gram-positive bacteria. We herein report production of analogues of two lantibiotics, lacticin 481 and nisin, that contain nonproteinogenic amino acids using two different strategies involving amber stop codon suppression technology. These methods complement recent alternative approaches to incorporate nonproteinogenic amino acids into lantibiotics...
April 20, 2018: ACS Chemical Biology
Francesco DI Pierro, Paolo Risso, Elena Poggi, Anna Timitilli, Sara Bolloli, Maurizio Bruno, Egidio Caneva, Riccardo Campus, Alessandro Giannattasio
BACKGROUND: Previous trials, performed in subjects affected by recurrent streptococcal pharyngo-tonsillar infection, have shown that the use for 90 days of Streptococcus salivarius K12 (K12), an oral colonizing probiotic producing lantibiotic bacteriocins, reduces the occurrence of streptococcal and viral pharyngitis and acute otitis media (AOM). The aim was to evaluate the role of K12 in reducing the incidence of streptococcal and viral pharyngo-tonsillitis and AOM when administered in two separate trimesters, from October to December and then from April to June, in pediatric subjects with non-recurrent streptococcal infection...
January 11, 2018: Minerva Pediatrica
Jin Hee Jeong, Sung Chul Ha
Nisin is a lantibiotic, a member of a family of polypeptides containing lanthionine with antimicrobial activity. Nisin-producing microorganisms require immunity proteins for self-protection from nisin itself. Lactococcus lactis , a microorganism that synthesizes nisin, has an integral NisFEG ABC transporter and an NisI lipoprotein that function in nisin immunity. Here, we present the crystal structure of the full length of NisI22-C , a lipid-free form of NisI, determined at 1.9-Å resolution. As with the nuclear magnetic resonance (NMR) structures of the N- and C-terminal domains of NisI, NisI22-C is composed of N- and C-terminal domains, both of which display a fold similar to that found in SpaI, a lipoprotein with immunity against subtilin in Bacillus subtilis The full-length structure of NisI22-c reveals a large, deep cleft by the interdomain association, one side of which is occupied by the residues important for immunity...
March 2018: Antimicrobial Agents and Chemotherapy
Li Zhang, Kunling Teng, Jian Wang, Zheng Zhang, Jie Zhang, Shutao Sun, Lili Li, Xiaopan Yang, Jin Zhong
Cerecidins are small lantibiotics from Bacillus cereus that were obtained using a semi- in vitro biosynthesis strategy and showed prominent antimicrobial activities against certain Gram-positive bacteria. However, the parental strain B. cereus As 1.1846 is incapable of producing cerecidins, most probably due to the transcriptional repression of the cerecidin gene cluster. Located in the cerecidin gene cluster, cerR encodes a putative response regulator protein that belongs to the LuxR family transcriptional regulators...
March 1, 2018: Applied and Environmental Microbiology
Giuseppe Gallo, Andrea Scaloni
Proteomics based on 2D-Difference In Gel Electrophoresis (2D-DIGE) coupled with mass spectrometry (MS) procedures can be considered a "gold standard" to determine quantitatively and comparatively protein abundances in cell extracts from different biological sources/conditions according to a gel-based approach. In particular, 2D-DIGE is used for protein specie separation, detection, and relative quantification, whenever tandem MS is used to obtain peptide sequence information that is managed according to bioinformatic procedures to identify the differentially represented protein species...
2018: Methods in Molecular Biology
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
Sen Zheng, Jun-Ichi Nagao, Mami Nishie, Takeshi Zendo, Kenji Sonomoto
Lantibiotic nukacin ISK-1 is produced by Staphylococcus warneri ISK-1. The dual functional transporter NukT, an ABC transporter maturation and secretion protein, contributes to cleavage of the leader peptide from the prepeptide (modified NukA) and the final transport of nukacin ISK-1. NukT consists of an N-terminal peptidase domain (PEP), a C-terminal nucleotide-binding domain (NBD), and a transmembrane domain (TMD). In this study, NukT and its peptidase-inactive mutant were expressed, purified, and reconstituted into liposomes for analysis of their peptidase and ATPase activities...
January 2018: Applied Microbiology and Biotechnology
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