Sulfur,selenium and tellurium pseudopeptides: Synthesis and biological evaluation

A new series of sulfur, selenium and tellurium peptidomimetic compounds was prepared employing the Passerini and Ugi isocyanide based multicomponent reactions (IMCRs). These reactions were clearly superior to conventional methods traditionally used for organoselenium and organotellurium synthesis, such as classical nucleophilic substitution and coupling methods. From the biological point of view, these compounds are of considerable interest because of suspected anticancer and antimicrobial activities. While the sulfur and selenium containing compounds generally did not show either anticancer or antimicrobial activities, their tellurium based counterparts frequently exhibited antimicrobial activity and were also cytotoxic. Some of the compounds synthesized even showed selective activity against certain cancer cells in cell culture. These compounds induced a cell cycle delay in the G0/G1 phase. At closer inspection, the ER and the actin cytoskeleton appeared to be the primary cellular targets of these tellurium compounds, in line with some of our previous studies. As most of these peptidomimetic compounds also comply with Lipinski’s Rule of Five, they promise good bioavailability, which needs to be studied as part of future investigations.     

稀土抗菌效应及应用的研究进展

稀土元素具有多种生物效应, 除了对农作物的增产作用外, 在医药方面还具有抗菌的作用, 近年来, 不少学者针对稀土元素的抗菌效应展开了相关的研究。本文介绍了稀土在抗菌领域的研究及应用, 包括稀土化合物对微生物生长的Hormesis效应、稀土化合物与抗生素的协同作用、稀土配合物的合成、以及稀土在抗菌材料上的应用等几个方面的内容, 并对稀土化合物及其配合物的抗菌机理进行了探讨, 最后, 展望了稀土化合物及配合物在抗菌领域的应用前景及研究重要性。     

What makes Allium species effective against pathogenic microbes?

The antimicrobial activity of garlic (Allium sativum L.) has been known since ancient times. The first citation dates back to the Egyptian period of fifteenth century BC when garlic was reported to be used in folk medicine as a remedy for microbial infections. Scientific investigations on garlic started in 1858 with the work of Pasteur who first noted antibacterial properties of garlic extracts. From that date to the discovery of antibiotics, garlic has been used against amoebic dysentery and epidemic diseases such as typhus, cholera, diphtheria, and tuberculosis. But what makes garlic and Allium species effective against pathogenic microbes? The volatile allicin and other thiosulfinates, giving pungency to Allium plants, are well-studied antimicrobial agents. The thiosulfinates can decompose to form additional sulfur constituents, including diallyl, methyl allyl, and dipropyl mono-, di-, tri- e tetra-sulfides, and (E)- and (Z)-ajoene without losing antimicrobial activity. Besides these compounds, onion and garlic are characterized by polar compounds of steroidal and phenolic origin, often glycosilated, not pungent and more stable during cooking, showing also antimicrobial activity. Recently, there has been increasing scientific attention given to such compounds. Nitrogen organic compounds, like alkaloids and polypeptides, have also been isolated from these plants and have shown antimicrobial activity. In this paper, the literature about the major volatile and non-volatile organic compounds of garlic and other Allium plants has been reviewed. Particular attention is given to the compounds possessing antimicrobial activity and to the correlation between the observed activity and the chemical structure of the tested compounds.     

Antimicrobial Phytoprotectants and Fungal Pathogens: A Commentary

Many plants produce antifungal secondary metabolites. These may be preformed compounds which are found in healthy plants and which may represent in-built chemical barriers to infection by potential pathogens (preformed antimicrobial compounds or phytoanticipins). Alternatively they may be synthesized in response to pathogen attack as part of the plant defence response (phytoalexins). If these molecules do play a role in protecting plants against pathogen attack, then successful pathogens are presumably able to circumvent or tolerate these defences. Strategies may include avoidance, enzymatic degradation, and/or nondegradative mechanisms. This review outlines the different ways in which fungal pathogens may counter the antifungal compounds produced by their host plants and summarizes the evidence for and against these compounds as antimicrobial phytoprotectants.     

Susceptibility and resistance of ruminal bacteria to antimicrobial feed additives

Susceptibility and resistance of ruminal bacterial species to avoparcin, narasin, salinomycin, thiopeptin, tylosin, virginiamycin, and two new ionophore antibiotics, RO22-6924/004 and RO21-6447/009, were determined. Generally, antimicrobial compounds were inhibitory to gram-positive bacteria and those bacteria that have gram-positive-like cell wall structure. MICs ranged from 0.09 to 24.0 micrograms/ml. Gram-negative bacteria were resistant at the highest concentration tested (48.0 micrograms/ml). On the basis of their fermentation products, ruminal bacteria that produce lactic acid, butyric acid, formic acid, or hydrogen were susceptible and bacteria that produce succinic acid or ferment lactic acid were resistant to the antimicrobial compounds. Selenomonas ruminantium was the only major lactic acid-producing bacteria resistant to all the antimicrobial compounds tested. Avoparcin and tylosin appeared to be less inhibitory (MIC greater than 6.0 micrograms/ml) than the other compounds to the two major lactic acid-producing bacteria, Streptococcus bovis and Lactobacillus sp. Ionophore compounds seemed to be more inhibitory (MIC, 0.09 to 1.50 micrograms/ml) than nonionophore compounds (MIC, 0.75 to 12.0 micrograms/ml) to the major butyric acid-producing bacteria. Treponema bryantii, an anaerobic rumen spirochete, was less sensitive to virginiamycin than to the other antimicrobial compounds. Ionophore compounds were generally bacteriostatic, and nonionophore compounds were bactericidal. The specific growth rate of Bacteroides ruminicola was reduced by all the antimicrobial compounds except avoparcin. The antibacterial spectra of the feed additives were remarkably similar, and it appears that MICs may not be good indicators of the potency of the compounds in altering ruminal fermentation characteristics.     

Susceptibility and resistance of ruminal bacteria to antimicrobial feed additives.

Susceptibility and resistance of ruminal bacterial species to avoparcin, narasin, salinomycin, thiopeptin, tylosin, virginiamycin, and two new ionophore antibiotics, RO22-6924/004 and RO21-6447/009, were determined. Generally, antimicrobial compounds were inhibitory to gram-positive bacteria and those bacteria that have gram-positive-like cell wall structure. MICs ranged from 0.09 to 24.0 micrograms/ml. Gram-negative bacteria were resistant at the highest concentration tested (48.0 micrograms/ml). On the basis of their fermentation products, ruminal bacteria that produce lactic acid, butyric acid, formic acid, or hydrogen were susceptible and bacteria that produce succinic acid or ferment lactic acid were resistant to the antimicrobial compounds. Selenomonas ruminantium was the only major lactic acid-producing bacteria resistant to all the antimicrobial compounds tested. Avoparcin and tylosin appeared to be less inhibitory (MIC greater than 6.0 micrograms/ml) than the other compounds to the two major lactic acid-producing bacteria, Streptococcus bovis and Lactobacillus sp. Ionophore compounds seemed to be more inhibitory (MIC, 0.09 to 1.50 micrograms/ml) than nonionophore compounds (MIC, 0.75 to 12.0 micrograms/ml) to the major butyric acid-producing bacteria. Treponema bryantii, an anaerobic rumen spirochete, was less sensitive to virginiamycin than to the other antimicrobial compounds. Ionophore compounds were generally bacteriostatic, and nonionophore compounds were bactericidal. The specific growth rate of Bacteroides ruminicola was reduced by all the antimicrobial compounds except avoparcin. The antibacterial spectra of the feed additives were remarkably similar, and it appears that MICs may not be good indicators of the potency of the compounds in altering ruminal fermentation characteristics.     

Isolation and characterization of antimicrobial food components

Nowadays there is an evident growing interest in natural antimicrobial compounds isolated from food matrices. According to the type of matrix, different isolation and purification steps are needed and as these active compounds belong to different chemical classes, also different chromatographic and electrophoretic methods coupled with various detectors (the most used diode array detector and mass spectrometer) have to be performed. This review covers recent steps made in the fundamental understanding of sample preparation methods as well as of analytical tools useful for the complete characterization of bioactive food compounds. The most commonly used methods for extraction of natural antimicrobial compounds are the conventional liquid-liquid or solid-liquid extraction and the modern techniques such as pressurized liquid extraction, microwave-assisted extraction, ultrasound-assisted extraction, solid-phase micro-extraction, supercritical fluid extraction, and matrix solid phase dispersion. The complete characterization of the compounds is achieved using both monodimensional chromatographic processes (LC, nano-LC, GC, and CE coupled with different type of detectors) and, recently, using comprehensive two-dimensional systems (LC×LC and GC×GC).     

Antimicrobial Effect of Red Clover (Trifolium pratense) Phenolic Extract on the Ruminal Hyper Ammonia-Producing Bacterium, Clostridium sticklandii

Ruminal proteolysis and subsequent amino acid degradation represent considerable economic loss in ruminant production. The hyper ammonia-producing bacteria (HAB) are largely responsible for amino acid deamination in the rumen. HAB can be controlled with ionophores, but they are also susceptible to antimicrobial plant secondary metabolites. Red clover (Trifolium pratense) is rich in soluble phenolics, and it is also more resistant to proteolysis than other legumes. The goal of this study was to identify phenolic compounds from Trifolium pratense cultivar Kenland, and determine if any of the compounds possessed antimicrobial activity against the bovine HAB, Clostridium sticklandii SR. HPLC analysis revealed that clover tissues were rich in the isoflavonoids formononetin and biochanin A, particularly in plants left to wilt for 24 h. Biochanin A inhibited C. sticklandii in bioassays that employed thin-layer chromatography (TLC). Both clover extracts and biochanin A inhibited the growth of C. sticklandii in broth culture, but formononetin had no effect. These results indicate that clover phenolic compounds may have a role in preventing amino acid fermentation.     

Are the short cationic lipopeptides bacterial membrane disruptors? Structure-Activity Relationship and molecular dynamic evaluation

Short cationic lipopeptides are amphiphilic molecules that exhibit antimicrobial activity mainly against Gram-positives. These compounds bind to bacterial membranes and disrupt their integrity. Here we examine the structure-activity relation (SAR) of lysine-based lipopeptides, with a prospect to rationally design more active compounds. The presented study aims to explain how antimicrobial activity of lipopeptides is affected by the charge of lipopeptide headgroup and the length of lipopeptide acyl chain. The obtained SAR models suggest that the lipophilicity of short synthetic cationic lipopeptides is the major factor that determines their antimicrobial activities. In order to link the differences in antimicrobial activity to the mechanism of action of lipopeptides containing one and two hydrophobic chains, we additionally performed molecular dynamic (MD) simulations. By using combined coarse-grained and all-atom simulations we also show that these compounds neither affect the organization of the membrane lipids nor aggregate to form separate phases. These results, along with the onset of antimicrobial activity of lipopeptides well below the critical micelle concentration (CMC), indicate that lipopeptides do not act in a simple detergent-like manner.     

A new effective assay to detect antimicrobial activity of filamentous fungi

The search for new antimicrobial compounds and the optimization of production methods turn the use of antimicrobial susceptibility tests a routine. The most frequently used methods are based on agar diffusion assays or on dilution in agar or broth. For filamentous fungi, the most common antimicrobial activity detection methods comprise the co-culture of two filamentous fungal strains or the use of fungal extracts to test against single-cell microorganisms. Here we report a rapid, effective and reproducible assay to detect fungal antimicrobial activity against single-cell microorganisms. This method allows an easy way of performing a fast antimicrobial screening of actively growing fungi directly against yeast. Because it makes use of an actively growing mycelium, this bioassay also provides a way for studying the production dynamics of antimicrobial compounds by filamentous fungi. The proposed assay is less time consuming and introduces the innovation of allowing the direct detection of fungal antimicrobial properties against single cell microorganisms without the prior isolation of the active substance(s). This is particularly useful when performing large screenings for fungal antimicrobial activity. With this bioassay, antimicrobial activity of Hypholoma fasciculare against yeast species was observed for the first time.     

Antimicrobial properties of allium species

The antimicrobial activity of Allium species has long been recognized, with allicin, other thiosulfinates, and their transformation products having antimicrobial activity. Alliums are inhibitory against all tested microorganisms such as bacteria, fungi, viruses, and parasites. Alliums inhibit multi-drug-resistant microorganisms and often work synergistically with common antimicrobials. Allium-derived antimicrobial compounds inhibit microorganisms by reacting with the sulfhydryl (SH) groups of cellular proteins. It used to be thought that allicin reacts only with cysteine and not with non-SH amino acids, but evidence has accumulated that allicin and other thiosulfinates also react with non-SH amino acids.     

New vinyl-1,2,4-triazole derivatives as antimicrobial agents: Synthesis,biological evaluation and molecular docking studies

1,2,4-Triazole is a very important scaffold in medicinal chemistry due to the wide spectrum of biological activities and mainly antifungal activity of 1,2,4-triazole derivatives. The main mechanism of antifungal action of the latter is inhibition of 14-alpha-demethylase enzyme (CYP51). The current study presents synthesis and evaluation of eight triazole derivatives for their antimicrobial activity. Docking studies to elucidate the mechanism of action were also performed. The designed compounds were synthesized using classical methods of organic synthesis. The in vivo evaluation of antimicrobial activity was performed by microdilution method. All tested compounds showed good antibacterial activity with MIC and MBC values ranging from 0.0002 to 0.0069 mM. Compound 2 h appeared to be the most active among all tested with MIC at 0.0002–0.0033 mM and MBC at 0.0004–0.0033 mM followed by compounds 2f and 2g. The most sensitive bacterium appeared to be Xanthomonas campestris while Erwinia amylovora was the most resistant. The evaluation of antifungal activity revealed that all compounds showed good antifungal activity with MIC values ranging from 0.02 mM to 0.52 mM and MFC from 0.03 mM to 0.52 mM better than reference drugs ketoconazole (MIC and MFC values at 0.28–1.88 mM and 0.38 mM to 2.82 mM respectively) and bifonazole (MIC and MFC values at 0.32–0.64 mM and 0.64–0.81 mM). The best antifungal activity is displayed by compound 2 h with MIC at 0.02–0.04 mM and MFC at 0.03–0.06 mM while compound 2a showed the lowest activity. The results showed that these compounds could be lead compounds in search for new potent antimicrobial agents. Docking studies confirmed experimental results.     

Antimicrobial compounds from Eremophila serrulata

We report a search for antimicrobial compounds in the Australian plant Eremophila serrulata. Bioassay directed fractionation of a diethyl ether extract prepared from the leaves of E. serrulata led to the isolation of two compounds, an omicron-naphthoquinone, 9-methyl-3-(4-methyl-3-pentenyl)-2,3-dihydronaphtho[1,8-bc]pyran-7,8-dione (2), and a serrulatane diterpenoid, 20-acetoxy-8-hydroxyserrulat-14-en-19-oic acid (3). Two other known serrulatane-type diterpenoids, 8,20-dihydroxyserrulat-14-en-19-oic acid (4) and 8,20-diacetoxyserrulat-14-en-19-oic acid (5) were also isolated. None of these compounds had previously been tested for antimicrobial activity. Compounds 2-5 showed antimicrobial activity against Staphylococcus aureus (ATCC 29213) with minimum inhibitory concentrations (MICs) ranging from 15.6 to 250mug/mL. Compound 2 was the most active with an MIC of 15.6mug/mL and a minimum bactericidal concentration (MBC) of 125mug/mL. This compound also showed antimicrobial activity against other Gram-positive bacteria including Streptococcus pyogenes, and Streptococcus pneumoniae. No activity was observed for this compound against all Gram-negative bacteria tested.     

Synthesis, biological evaluation of 5-carbomethoxymethyl-7-hydroxy-2-pentylchromone, 5-carboethoxymethyl-4',7-dihydroxyflavone and their analogues

In this letter, we describe the first synthesis of two recently isolated flavones 5-carbomethoxymethyl-7-hydroxy-2-pentylchromone (3a), 5-carboethoxymethyl-4',7-dihydroxyflavone (3b) and their derivatives (3c-t), evaluated for their antimicrobial, antioxidant and anticancer activities. Most of the synthesized compounds exhibited antimicrobial activity against the tested microbial strains and some of these compounds were found to be more potent as compared to the standard drugs like neomycin and luteolin. Interestingly, some of these synthesized compounds also showed moderate antioxidant property.     

Computational Ranking of Yerba Mate Small Molecules Based on Their Predicted Contribution to Antibacterial Activity against Methicillin-Resistant Staphylococcus aureus

The aqueous extract of yerba mate, a South American tea beverage made from Ilex paraguariensis leaves, has demonstrated bactericidal and inhibitory activity against bacterial pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). The gas chromatography-mass spectrometry (GC-MS) analysis of two unique fractions of yerba mate aqueous extract revealed 8 identifiable small molecules in those fractions with antimicrobial activity. For a more comprehensive analysis, a data analysis pipeline was assembled to prioritize compounds for antimicrobial testing against both MRSA and methicillin-sensitive S. aureus using forty-two unique fractions of the tea extract that were generated in duplicate, assayed for activity, and analyzed with GC-MS. As validation of our automated analysis, we checked our predicted active compounds for activity in literature references and used authentic standards to test for antimicrobial activity. 3,4-dihydroxybenzaldehyde showed the most antibacterial activity against MRSA at low concentrations in our bioassays. In addition, quinic acid and quercetin were identified using random forests analysis and 5-hydroxy pipecolic acid was identified using linear discriminant analysis. We also generated a ranked list of unidentified compounds that may contribute to the antimicrobial activity of yerba mate against MRSA. Here we utilized GC-MS data to implement an automated analysis that resulted in a ranked list of compounds that likely contribute to the antimicrobial activity of aqueous yerba mate extract against MRSA.     

Antimicrobial substances from rhizomes of the giant knotweed Polygonum sachalinense against the fish pathogen Photobacterium damselae subsp. piscicida

The antimicrobial compounds against the fish pathogen Photobacterium damselae subsp. piscicida were isolated from Polygonum sachalinense rhizomes. The structures of the antimicrobial compounds 1 and 2 were determined by 1H and 13C NMR, 2D-NMR (COSY, HSQC, HMBC and ROESY) and FAB-MS to be phenylpropanoid glycosides, vanicoside A and B, respectively. Both compounds have feruloyl and p-coumaroyl groups bonded to a sucrose moiety in their structures. Vanicoside A also has an acetyl group in the sucrose moiety. The MIC values for vanicoside A and B against Ph. damselae subsp. piscicida DPp-1 were 32 and 64 microg/ml, respectively. The antimicrobial activities of these vanicosides were modest, in contrast to higher activities (MICs at < 4 microg/ml) of antibiotics, florphenicol, ampicillin and amoxicillin, which have been generally used for treating pasteurellosis. The activities of the vanicosides, however, were higher than those (MICs at 256 microg/ml) of ferulic acid and p-coumaric acid. It was suggested that the structure of phenylpropanoids esterified with sucrose was essential for higher antimicrobial activity of vanicosides and also acetylation of sucrose might affect the activity against the bacterium.     

The isoprostanoid pathway in plants

Higher plants are generally unable to synthesize arachidonic acid, and thus, do neither form prostaglandins nor C20-isoprostanes. Instead, plants utilize linolenic acid for the synthesis of prostaglandin-like compounds of the jasmonate type via the lipoxygenase/allene oxide synthase pathway and C18-isoprostanoids, termed phytoprostanes, via a nonenzymatic, free radical catalyzed pathway analogous to the isoprostane pathway in animals. Both pathways are constitutively present in many if not all plants. Formation of jasmonates can be triggered by specific stimuli interacting with membrane receptors while phytoprostane synthesis can be induced by ROS and heavy metals. Jasmonates are established plant signal compounds that induce defense responses including accumulation of antimicrobial secondary metabolites (phytoalexins). Preliminary data indicates that phytoprostanes also induce phytoalexins in a variety of plant species suggesting a possible function of phytoprostanes as mediators of defense reactions in response to oxidative stress in plants.     

A novel synthesis and antimicrobial activity of 1-[(Substituted-phenyl) sulfonyl]pyrrolidin-2-ones

Novel cyclization of 4-(substituted-phenylsulfonamido)butanoic acids to their corresponding 1-[(substituted-phenyl)sulfonyl]pyrrolidin-2-ones was successfully achieved by using polyphosphate ester (PPE). The reaction time was considerably reduced with corresponding increase in the yields, when polyphosphate ester (PPE) was used in combination with 4-(N,N-dimethylamino)pyridine (DMAP). All the synthesized compounds were screened for their antimicrobial activity. Minimum Inhibitory Concentration (MIC) values of synthesized compounds were also determined, and were found to be in the range of 0.09-1.0 mg.     

Identification of antimicrobial peptide regions derived from genomic sequences of phage lysins

This study was designed to test the possibility that antimicrobial peptides could be derived from the genomic sequences of phage lysins. Using two lysins (D3 and PhiKZ) we selected and produced two putative peptides (X and Z, respectively) believed to possess antimicrobial properties based on their physicochemical characteristics. The data presented support this hypothesis in that the peptides and various analogs displayed antibacterial activity, bacteriostatic or bactericidal, either individually or upon combination. These putative peptides are believed to act by a mechanism of action resembling that of conventional antimicrobial peptides when judged by both structural and functional criteria. Thus, the peptides are shown to have the ability to form a helical structure, to bind to model bacterial membranes and permeabilize model liposomes. They also display rapid bactericidal kinetics and their antibacterial potency is increased upon amidation. The possible relevance of these results in contributing to potency of phage lysins is discussed. Such peptides may be used to design new potent antimicrobial compounds much needed in face of the ever threatening drug resistance problems.