Antibacterial Natural Products Research Articles

Stereospecific Synthesis of the Saccharosamine-Rhamnose-Fucose Fragment Present in Saccharomicin B.

A synthetic route has been developed for constructing the d-saccharosamine-l-rhamnose-d-fucose (Sac-Rha-Fuc) trisaccharide fragment present in the antibacterial natural product saccharomicin B. The Sac monosaccharide was synthesized through a modified nine step procedure starting from d-rhamnal in 23% overall yield. 1- O-TBS Sac donors were used to construct the β-linked Sac-Rha disaccharide. This disaccharide was coupled to a Fuc acceptor under BSP/Tf2O conditions to afford a trisaccharide properly functionalized for elaboration to saccharomicin B.

Self-Resistance during Muraymycin Biosynthesis: a Complementary Nucleotidyltransferase and Phosphotransferase with Identical Modification Sites and Distinct Temporal Order.

Muraymycins are antibacterial natural products from Streptomyces spp. that inhibit translocase I (MraY), which is involved in cell wall biosynthesis. Structurally, muraymycins consist of a 5'-C-glycyluridine (GlyU) appended to a 5″-amino-5″-deoxyribose (ADR), forming a disaccharide core that is found in several peptidyl nucleoside inhibitors of MraY. For muraymycins, the GlyU-ADR disaccharide is further modified with an aminopropyl-linked peptide to generate the simplest structures, annotated as the muraymycin D series. Two enzymes encoded in the muraymycin biosynthetic gene cluster, Mur29 and Mur28, were functionally assigned in vitro as a Mg·ATP-dependent nucleotidyltransferase and a Mg·ATP-dependent phosphotransferase, respectively, both modifying the 3″-OH of the disaccharide. Biochemical characterization revealed that both enzymes can utilize several nucleotide donors as cosubstrates and the acceptor substrate muraymycin also behaves as an inhibitor. Single-substrate kinetic analyses revealed that Mur28 preferentially phosphorylates a synthetic GlyU-ADR disaccharide, a hypothetical biosynthetic precursor of muraymycins, while Mur29 preferentially adenylates the D series of muraymycins. The adenylated or phosphorylated products have significantly reduced (170-fold and 51-fold, respectively) MraY inhibitory activities and reduced antibacterial activities, compared with the respective unmodified muraymycins. The results are consistent with Mur29-catalyzed adenylation and Mur28-catalyzed phosphorylation serving as complementary self-resistance mechanisms, with a distinct temporal order during muraymycin biosynthesis.

Biosynthesis of thiocarboxylic acid-containing natural products

Thiocarboxylic acid-containing natural products are rare and their biosynthesis and biological significance remain unknown. Thioplatensimycin (thioPTM) and thioplatencin (thioPTN), thiocarboxylic acid congeners of the antibacterial natural products platensimycin (PTM) and platencin (PTN), were recently discovered. Here we report the biosynthetic origin of the thiocarboxylic acid moiety in thioPTM and thioPTN. We identify a thioacid cassette encoding two proteins, PtmA3 and PtmU4, responsible for carboxylate activation by coenzyme A and sulfur transfer, respectively. ThioPTM and thioPTN bind tightly to β-ketoacyl-ACP synthase II (FabF) and retain strong antibacterial activities. Density functional theory calculations of binding and solvation free energies suggest thioPTM and thioPTN bind to FabF more favorably than PTM and PTN. Additionally, thioacid cassettes are prevalent in the genomes of bacteria, implicating that thiocarboxylic acid-containing natural products are underappreciated. These results suggest that thiocarboxylic acid, as an alternative pharmacophore, and thiocarboxylic acid-containing natural products may be considered for future drug discovery.

Capturing antibacterial natural products with insilico techniques.

The aim of the present study was to index natural products in order to facilitate the discovery of less expensive antibacterial therapeutic drugs. Thus, for modeling purposes, the present study utilized a set of 628 antibacterial drugs, representing the active domain, and 2,892 natural products, representing the inactive domain. In addition, using the iterative stochastic elimination algorithm, 36 unique filters were identified, which were then used to construct a highly discriminative and robust model tailored to index natural products for their antibacterial bioactivity. The area attained under the curve was 0.957, indicating a highly discriminative and robust prediction model. Utilizing the proposed model to virtually screen a mixed set of active and inactive substances enabled the present study to capture 72% of the antibacterial drugs in the top 1% of the sample, yielding an enrichment factor of 72. In total, 10 natural products that scored highly as antibacterial drug candidates with the proposed indexing model were reported. PubMed searches revealed that 2 molecules out of the 10 (caffeine and ricinine) have been tested and identified as showing antibacterial activity. The other 8 phytochemicals await experimental evaluation. Due to the efficiency and rapidity of the proposed prediction model, it could be applied to the virtual screening of large chemical databases to facilitate the drug discovery and development processes for antibacterial drug candidates.

Antimicrobial effects of propolis on Clostridium difficile strains belonging to the different PCR-ribotypes

<p><em>Clostridium difficile</em> is a Gram-positive, anaerobic rod-shaped bacterium, which is a primary cause of nosocomial diarrhoea. The rising incidence of antibiotic resistance in pathogens such as <em>C. difficile</em> makes the new antibacterial natural products research very important and necessary to conduct. It has been observed that propolis has bactericidal effects<em>.</em> Propolis is a natural resinous product that is manufactured by honeybees (<em>Apis mellifera</em>). The antimicrobial activity of propolis is an important biological property. In spite of the large composition differences of the propolis types, all of them have antimicrobial activity. Twenty strains of the <em>C.difficile</em> belonging to four prominent PCR-ribotypes (RT) (RT017, RT023, RT027, and RT046) were used in research. MBC value were determined by broth dilution method. Propolis samples were obtained from honey bees farm in lubelskie woyevodship. Bactericidal effect of the propolis on <em>C.difficile</em> strains was observed at its concentration of 39 mg/ml.</p>

Scalable Access to Arylomycins via C-H Functionalization Logic.

Arylomycins are a promising class of “latent” antibacterial natural products currently in preclinical development. Access to analogues within this family has previously required a lengthy route involving multiple functional group manipulations that is costly and time-intensive on scale. This study presents a simplified route predicated on simple C–H functionalization logic that is enabled by a Cu-mediated oxidative phenol coupling that mimics the putative biosynthesis. This operationally simple macrocyclization is the largest of its kind and can be easily performed on gram scale. The application of this new route to a formal synthesis of the natural product and a collection of new analogues along with their biological evaluation is also reported.

Biomimetic Total Syntheses of Callistrilones A, B, and D.

A biomimetic total syntheses of antibacterial natural products (±)-callistrilones A, B, and D, the first triketone-phloroglucinol-monoterpene hybrids with an unprecedented [1]benzofuro[2,3-a]xanthene and [1]benzofuro[3,2-b]xanthene pentacyclic ring system along with the postulated biosynthetic intermediate, isolated from the leaves of Callistemon rigidus, were achieved. The total synthesis features highly regio- and diastereoselective catalytic Friedel-Crafts alkylation, palladium-catalyzed Wacker-type oxidative cyclization, Michael addition, and late-stage diastereoselective epoxide formation from the extremely hindered β face as key steps.

Enantiospecific sp2 -sp3 Coupling of ortho- and para-Phenols with Secondary and Tertiary Boronic Esters.

The coupling of ortho‐ and para‐phenols with secondary and tertiary boronic esters has been explored. In the case of para‐substituted phenols, after reaction of a dilithio phenolate species with a boronic ester, treatment with Ph3BiF2 or Martin's sulfurane gave the coupled product with complete enantiospecificity. The methodology was applied to the synthesis of the broad spectrum antibacterial natural product (−)‐4‐(1,5‐dimethylhex‐4‐enyl)‐2‐methyl phenol. For ortho‐substituted phenols, initial incorporation of a benzotriazole on the phenol oxygen atom was required. Subsequent ortho‐lithiation and borylation gave the coupled product, again with complete stereospecificity.

Enantiospecific sp2–sp3 Coupling of ortho‐ and para‐Phenols with Secondary and Tertiary Boronic Esters

AbstractThe coupling of ortho‐ and para‐phenols with secondary and tertiary boronic esters has been explored. In the case of para‐substituted phenols, after reaction of a dilithio phenolate species with a boronic ester, treatment with Ph3BiF2 or Martin's sulfurane gave the coupled product with complete enantiospecificity. The methodology was applied to the synthesis of the broad spectrum antibacterial natural product (−)‐4‐(1,5‐dimethylhex‐4‐enyl)‐2‐methyl phenol. For ortho‐substituted phenols, initial incorporation of a benzotriazole on the phenol oxygen atom was required. Subsequent ortho‐lithiation and borylation gave the coupled product, again with complete stereospecificity.

Total Syntheses of Cystobactamids and Structural Confirmation of Cystobactamid 919-2.

The cystobactamids are a family of antibacterial natural products with unprecedented chemical scaffolds that are active against both Gram-positive and Gram-negative pathogens. Herein, we describe the first total synthesis of cystobactamid 919-2 from three fragments. Our convergent synthesis enabled both the confirmation of the correct structure and the determination of the absolute configuration of cystobactamid 919-2.

Total Syntheses of Cystobactamids and Structural Confirmation of Cystobactamid 919‐2

AbstractThe cystobactamids are a family of antibacterial natural products with unprecedented chemical scaffolds that are active against both Gram‐positive and Gram‐negative pathogens. Herein, we describe the first total synthesis of cystobactamid 919‐2 from three fragments. Our convergent synthesis enabled both the confirmation of the correct structure and the determination of the absolute configuration of cystobactamid 919‐2.

Natural Substances in the Treatment of Cystic Fibrosis

The research on the biological activity of natural products and biomaterials is becoming year by year more competitive and complex, and involves experts in different research fields, including chemists, biochemists, molecular biologists, immunologists and bioinformatics. While unfractionated natural products exhibit “per se” biological properties relevant for alternative therapeutic treatments of human diseases, the identification of lead compounds within these products, the characterization of molecular targets and studies of structurally-related molecules are key processes to develop novel therapeutic strategies. Cystic fibrosis is a genetic disease caused by mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. It is well established that three major fields of therapeutic intervention should be considered, targeting CFTR, bacterial infection and inflammation. In this review, we describe natural products reported to be very useful tools for correction of pathological conditions related to cystic fibrosis. The main topics are (a) CFTR potentiation and correction using natural products, (b) natural products as antibacterial agents and (c) natural products exhibiting anti-inflammatory activity. The recent issues of waste utilization and drug repurposing are also discussed in the context of the development of possible therapeutic approaches for cystic fibrosis. Keywords: Cystic fibrosis, CFTR potentiation, CFTR correction, inflammation, antibacterial agents, drug repurposing.

Synthesis of Chromones from 1,1-Diacylcyclopropanes: Toward the Synthesis of Bromophycoic Acid E.

A tandem deprotection-cyclization reaction of 1,1-diacylcyclopropanes is described which allows rapid access to structurally diverse 2,3-disubstituted chromones in good yields, and with straightforward purification. The utility of this reaction is showcased by the construction of the potent antibacterial marine natural product bromophycoic acid E scaffold.

Synthesis and biological evaluation of the ascidian blood-pigment halocyamine A.

Synthesis of the antimicrobial marine natural product halocyamine A has been achieved utilizing a combination of Sonogashira coupling, ruthenium complex/ytterbium triflate catalyzed hydroamidation and solid-phase peptide synthesis (SPPS) chemistry. The synthetic natural product exhibited only modest levels of antibacterial activities but significant antioxidant activity.

Divergent Synthesis of Quinolone Natural Products from Pseudonocardia sp. CL38489.

Two divergent synthetic routes are reported offering access to four quinolone natural products from Pseudonocardia sp. CL38489. Key steps to the natural products involved a regioselective epoxidation, an intramolecular Buchwald–Hartwig amination and a final acid‐catalysed 1,3‐allylic‐alcohol rearrangement to give two of the natural products in one step. This study completes the synthesis of all eight antibacterial quinolone natural products reported in the family. In addition, this modular strategy enables an improved synthesis towards two natural products previously reported.

David J. Procter

Angewandte Chemie International EditionVolume 56, Issue 19 p. 5152-5152 Author ProfileFree Access David J. Procter First published: 07 November 2016 https://doi.org/10.1002/anie.201610197AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Graphical Abstract “The biggest challenge facing scientists is conformity. Looking back over my career, I remember the excitement of setting up my research laboratory and building my first team ...” This and more about David J. Procter can be found on page 5152. David J. Procter The author presented on this page has published more than 10 articles in Angewandte Chemie in the last 10 years, most recently: “Selective Synthesis of Cyclooctanoids by Radical Cyclization of Seven-Membered Lactones: Neutron Diffraction Study of the Stereoselective Deuteration of a Chiral Organosamarium Intermediate”: X. Just-Baringo, J. Clark, M. J. Gutmann, D. J. Procter, Angew. Chem. Int. Ed. 2016, 55, 12499; Angew. Chem. 2016, 128, 12687. Date of birth: September 4, 1970 Position: Professor of Organic Chemistry, University of Manchester E-mail: david.j.procter@manchester.ac.uk Homepage: http://people.man.ac.uk/∼mbdssdp2/ ORCID: 0000-0003-3179-2509 Education: 1992 BSc, University of Leeds 1995 PhD supervised by Christopher Rayner, University of Leeds 1995–1997 Postdoctoral research with Robert Holton, Florida State University Awards: 2014 Bader Award, Royal Society of Chemistry; 2014 Liebig Lectureship, Gesellschaft Deutscher Chemiker (GDCh; German Chemical Society); 2015 EPSRC Established Career Fellowship Research: Radical cyclizations and cascade reactions; organosulfur chemistry; copper catalysis Hobbies: My family, football, gardening The biggest challenge facing scientists is conformity. Looking back over my career, I remember the excitement of setting up my research laboratory and building my first team. My favorite drink is Robinsons Unicorn light ale from nearby Stockport. My favorite quote is “don't put off until tomorrow what you can do today” (My Dad and Benjamin Franklin, I believe). My biggest inspiration is my young family; the children put a smile on my face even after a tough day. My favorite time of day is early morning: I set the alarm for 5 am so I can work before breakfast. I advise my students to be creative and always follow up on the unexpected. My favorite way to spend a holiday is walking in the Lake District or on the beaches of Gower peninsula, Wales. My science “heroes” are Henri Kagan, who developed my favorite reagent, and so much more, and K. C. Nicolaou, the maker of high-profile natural products during my student days. The most important thing I learned from my students is that everyone sees chemistry differently. My favorite band … when growing up in Lancashire in the 1980s had to be The Smiths. My favorite book is Ernest Hemingway's The Old Man and The Sea, having recently re-read the story with my son. When I was eighteen I wanted to be the new Morrissey, minus the celibacy and the gladioli. My 5 top papers: References 1“Metal-Free CH−CH-Type Cross-Coupling of Arenes and Alkynes Directed by a Multifunctional Sulfoxide Group”: J. A. Fernández-Salas, A. J. Eberhart, D. J. Procter, J. Am. Chem. Soc. 2016, 138, 790. (Organosulfur chemistry meets a challenge in synthesis.) 2“Enantioselective Generation of Adjacent Stereocenters in a Copper-Catalyzed Three-Component Coupling of Imines, Allenes, and Diboranes”: K. Yeung, R. E. Ruscoe, J. Rae, A. P. Pulis, D. J. Procter, Angew. Chem. Int. Ed. 2016, 55, 11912; Angew. Chem. 2016, 128, 12091. (Complex homoallylic amines selectively obtained in one pot using a copper catalyst.) 3“Reductive Cyclization Cascades of Lactones Using SmI2–H2O”: D. Parmar, K. Price, M. Spain, H. Matsubara, P. A. Bradley, D. J. Procter, J. Am. Chem. Soc. 2011, 133, 2418. (Complexity generating cascade reactions involving unusual radical intermediates.) 4“A Dialdehyde Cyclization Cascade in an Approach to Pleuromutilin”: M. D Helm, M. Da Silva, D. Sucunza, T. J. K. Findley, D. J. Procter, Angew. Chem. Int. Ed. 2009, 48, 9315; Angew. Chem. 2009, 121, 9479. (A prelude to our total synthesis of the antibacterial natural product.) 5“A Fluorous-Phase Pummerer Cyclative-Capture Strategy for the Synthesis of Nitrogen Heterocycles”: L. A. McAllister, R. A. McCormick, S. Brand, D. J. Procter, Angew. Chem. Int. Ed. 2005, 44, 452; Angew. Chem. 2005, 117, 456. (New Pummerer reactions, an oxindole synthesis, and a novel tagging strategy.) Volume56, Issue19May 2, 2017Pages 5152-5152 ReferencesRelatedInformation

Antibacterial polyketides from Bacillus amyloliquefaciens associated with edible red seaweed Laurenciae papillosa

Heterotrophic Bacillus amyloliquefaciens associated with edible red seaweed, Laurenciae papillosa was used to isolate antibacterial polyketide compounds. Antibacterial activity studies integrated with the outcome obtained by polyketide synthetase (pks) coding genes established that seaweed-affiliated bacterial flora had a wide-ranging antibacterial activities and potential natural product diversity, which proved that the bacterium is valuable reservoir of novel bioactive metabolites. Bioactivity-guided isolation of 3-(octahydro-9-isopropyl-2H-benzo[h]chromen-4-yl)-2-methylpropyl benzoate and methyl 8-(2-(benzoyloxy)-ethyl)-hexahydro-4-((E)-pent-2-enyl)-2H-chromene-6-carboxylate of polyketide origin, with activity against human opportunistic food pathogenic microbes, have been isolated from the ethyl acetate extract of B. amyloliquefaciens. Structure-activity relationship analysis revealed that hydrophobic descriptor of the polyketide compounds significantly contribute towards its antibacterial activity. Seaweed-associated microorganisms were shown to represent a potential source of antimicrobial compounds for food and health benefits. The antibacterial polyketide compounds described in the present study may find potential applications in the food industry to reduce food-borne pathogens.

ChemInform Abstract: Function‐Oriented Synthesis: How to Design Simplified Analogues of Antibacterial Nucleoside Natural Products?

AbstractReview: [39 refs.

UJI ANTIBAKTERI EKSTRAK JAHE MERAH Zingiber officinale var. Rubrum TERHADAP Staphylococcus aureus DAN Escherichia coli

The study of inhibition testing antibacterial extract Fresh Red Ginger Zingiber officinale var. Rubrum Against Staphylococcus aureus, and Escherichia coliguna to determine the source of antibacterial natural products, especially red ginger has been conducted. Anti-bacterial inhibition test using disc diffusion method with fresh red ginger rhizome material. The study was conducted using concentrations: 0%, 20%, 40%, 60%, 80%, and 100%. Concentration of 0% was used as a negative control. The data obtained will be tested statistically using ANOVA with sig. 0.05. The results showed that the extraction of fresh red ginger (Zingiber officinale var. Rubrum) at a concentration of 100% has the highest inhibitory region to S. aureus (15.83 mm)and E. coli (14:22 mm). It can be concluded that the extract of fresh red ginger Zingiber officinale var. Rubrum at a concentration of 100% has a moderate level of inhibition to S. aureus and weak level of inhibition to E. coli.
 Keywords: Escherichia coli, Fresh red ginger extract of Zingiber officinale var. Rubrum, Staphylococcus aureus.

Function-Oriented Synthesis: How to Design Simplified Analogues of Antibacterial Nucleoside Natural Products?

It is important to pursue function-oriented synthesis (FOS), a strategy for the design of less structurally complex targets with comparable or superior activity that can be made in a practical manner, because compared to synthetic drugs, many biologically relevant natural products possess large and complex chemical structures that may restrict chemical modifications in a structure-activity relationship study. In this account, we describe recent efforts to simplify complex nucleoside natural products including caprazamycins. Considering the structure-activity relationship study with several truncated analogues, three types of simplified derivatives, namely, oxazolidine, isoxazolidine, and lactam-fused isoxazolidine-containing uridine derivatives, were designed and efficiently synthesized. These simplified derivatives have exhibited promising antibacterial activities. A significant feature of our studies is the rational and drastic simplification of the molecular architecture of caprazamycins. This study provides a novel strategy for the development of a new type of antibacterial agent effective against drug-resistant bacteria.