组合化学方法合成1，3，5-三嗪类化合物及其抗菌活性研究

基于天然或合成抗菌肽具有疏水性及带正电荷的特性,本研究以1,3,5-三嗪作为母体,利用组合化学方法合成了一系列三嗪衍生物。抗菌试验证明这些衍生物具有很强的抗菌活性和低溶血性,并能在低于最低抑菌浓度的情况下有效抑制细菌生物膜的生长。     

Antimicrobial effect of phlorotannins from marine brown algae

Marine organisms exhibit a rich chemical content that possess unique structural features as compared to terrestrial metabolites. Among marine resources, marine algae are a rich source of chemically diverse compounds with the possibility of their potential use as a novel class of artificial food ingredients and antimicrobial agents. The objective of this brief review is to identify new candidate drugs for antimicrobial activity against food-borne pathogenic bacteria. Bioactive compounds derived from brown algae are discussed, namely phlorotannins, that have anti-microbial effects and therefore may be useful to explore as potential antimicrobial agents for the food and pharmaceutical industries.     

Aspects of the antimicrobial efficacy of grapefruit seed extract and its relation to preservative substances contained.

The antimicrobial efficacy as well as the content of preservative agents of six commercially available grapefruit seed extracts were examined. Five of the six extracts showed a high growth inhibiting activity against the test germs Bacillus subtilis SBUG 14, Micrococcus flavus SBUG 16, Staphylococcus aureus SBUG 11, Serratia marcescens SBUG 9, Escherichia coli SBUG 17, Proteus mirabilis SBUG 47, and Candida maltosa SBUG 700. In all of the antimicrobial active grapefruit seed extracts, the preservative benzethonium chloride was detected by thin layer chromatography. Additionally, three extracts contained the preserving substances triclosan and methyl parabene. In only one of the grapefruit seed extracts tested no preservative agent was found. However, with this extract as well as with several self-made extracts from seed and juiceless pulp of grapefruits (Citrus paradisi) no antimicrobial activity could be detected (standard serial broth dilution assay, agar diffusion test). Thus, it is concluded that the potent as well as nearly universal antimicrobial activity being attributed to grapefruit seed extract is merely due to the synthetic preservative agents contained within. Natural products with antimicrobial activity do not appear to be present.     

Evaluation of microalgae and cyanobacteria as potential sources of antimicrobial compounds

In recent decades, marine microorganisms have become known for their ability to produce a wide variety of secondary bioactive metabolites. Several compounds have been isolated from marine microorganisms for the development of novel bioactives for the food and pharmaceutical industries. In this study, a number of microalgae were evaluated for their antimicrobial activity against gram-positive and gram-negative bacteria, including food and plant pathogens, using various extraction techniques and antimicrobial assays. Disc diffusion and spot-on-lawn assays were conducted to confirm the antimicrobial activity. To measure the potency of the extracts, minimum inhibition concentrations (MIultCs) were measured. Three microalgae, namely Isochrysis galbana, Scenedesmus sp. NT8c, and Chlorella sp. FN1, showed strong inhibitory activity preferentially against gram-positive bacteria. These microalgal species were then selected for further purification and analysis, leading to compound identification. By using a mixture of different chromatography techniques gas chromatography–mass spectrometry (GC–MS) and high-performance liquid chromatography (HPLC) and ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS), we were able to separate and identify the dominant compounds that are responsible for the inhibitory activity. Additionally, nuclear magnetic resonance (NMR) was used to confirm the presence of these compounds. The dominant compounds that were identified and purified in the extracts are linoleic acid, oleic acid, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). These compounds are the potential candidates that inhibit the growth of gram-positive bacteria. This indicates the potential use of microalgae and their antimicrobial compounds as biocontrol agents against food and plant pathogens.     

In vitro assays of the antibacterial and antioxidant activity of aqueous leaf extracts from different Prunus salicina Lindl. cultivars

The growing interest in the substitution of synthetic food antioxidants and antimicrobial additives by natural ones has fostered research on vegetable sources and on the screening of raw materials, for identifying new antioxidants and antimicrobial natural agents. The aim of the present study was to assess total phenolic contents and determine polyphenolic composition, related antioxidative and antimicrobial properties of plum leaves extracts from six cultivars. It was observed that the content of total phenolic compounds was cultivar dependent. High antioxidant capacity has been observed and related to the relative amounts of polyphenolic compounds with good antioxidant properties. The antimicrobial activity was confirmed against Listeria innocua and Escherichia coli, and it has found to be related with the high phenolic contents. Our results suggest that the use of plum leaf extracts is a feasible alternative as antibacterial and antioxidant agents to prevent the deterioration of stored foods by bacteria and oxidation.     

Antimicrobial peptides: Their physicochemical properties and therapeutic application

Antibiotic resistance has become a global public health problem, thus there is a need to develop a new class of antibiotics. Natural antimicrobial peptides have got an increasing attention as potential therapeutic agents. Antimicrobial peptides are small cationic peptides with broad antimicrobial activity. They can serve as critical defense molecules protecting the host from the invasion of bacteria. Even though they possess a different mode of action compared to traditional antibiotics, antimicrobial peptides couldn’t go into the drug markets because of problems in application such as toxicity, susceptibility to proteolysis, manufacturing cost, size, and molecular size. Nevertheless, antimicrobial peptides can be new hope in developing novel, effective and safe therapeutics without antibiotic resistance. Thus, it is necessary to discover new antimicrobial sources in nature and study their structures and physicochemical properties more in depth.     

New advances in anti-HSV chemotherapy

Treatment of human herpes simplex virus (HSV) diseases represents an important goal, as herpetic infections are not controlled by vaccination. Many therapeutic agents have been developed and used for HSV infections and several alternative natural compounds are under investigation. Most of the drugs clinically employed against HSV types 1 and 2 are represented by guanosine nucleoside analogues, such as aciclovir and aciclovir-like drugs. The emergence of aciclovir-resistant virus strains provided a stimulus for increased search of new effective agents. Alternative drugs are other nucleoside analogues, such as the vidarabine, brivudin, and cidofovir, or pyrophosphate analogues such as foscarnet, that showed efficacy for HSV infections refractory to aciclovir. However, the risk of adverse effects reported for available anti-herpetic compounds and the frequent development of drug-resistant strains of HSV following therapeutic treatment generate the need for new antiviral agents. In the last years, several studies have been carried out on the anti-HSV activity of different components of innate host defences such as cationic antimicrobial peptides. The antiviral activity of these peptides often appears to be related to the viral adsorption and entry process or is a result of a direct effect on the viral envelope. Other natural compounds, extracts from medicinal plants employed in ethnomedicine and displaying marked anti-herpetic activity, are at present under investigation to determine the scientific evidence and rationale for their clinical use. This review discusses the anti-HSV activity of compounds licensed for clinical use and promising natural molecules.     

Antimicrobial and demelanizing activity of Ganoderma lucidum extract,p-hydroxybenzoic and cinnamic acids and their synthetic acetylated glucuronide methyl esters

Mushroom extracts or isolated compounds may be useful in the search of new potent antimicrobial agents. Herein, it is described the synthesis of protected (acetylated) glucuronide derivatives of p-hydroxybenzoic and cinnamic acids, two compounds identified in the medicinal mushroom Ganoderma lucidum. Their antimicrobial and demelanizing activities were evaluated and compared to the parent acids and G. lucidum extract. p-Hydroxybenzoic and cinnamic acids, as also their protected glucuronide derivatives revealed high antimicrobial (antibacterial and antifungal) activity, even better than the one showed by commercial standards. Despite the variation in the order of parent acids and the protected glucuronide derivatives, their antimicrobial activity was always higher than the one revealed by the extract. Nevertheless, the extract was the only one with demelanizing activity against Aspergillus niger. The acetylated glucuronide derivatives could be deprotected to obtain glucuronide metabolites, which circulate in the human organism as products of the metabolism of the parent compounds.     

Antimicrobial compounds of low molecular mass are constitutively present in insects: characterisation of beta-alanyl-tyrosine

The number of bacterial and fungal strains that have developed resistance against the classical antibiotics continues to grow. The intensified search for new antibiotic lead compounds has resulted in the discovery of numerous endogenous peptides with antimicrobial properties in plants, bacteria and animals. Their possible applications as anti-infective agents are often limited by their size, in reference to production costs and susceptibility to proteases. In this article, we report recent isolations of antimicrobial compounds from insects, with molecular masses less than 1 kDa. Experimental approaches are discussed and the first data on the antimicrobial properties of beta-alanyl-tyrosine (252 Da), one of such low molecular mass compounds isolated from the fleshfly Neobellieria bullata, are presented. We also offer evidence for the constitutive presence of antimicrobial compounds in insects of different orders, in addition to the previously identified inducible antimicrobial peptides.     

昆虫提取物的抗菌活性研究

相对于植物化学和海洋生物化学,昆虫次生代谢物的多样性可能是新药研究中一个更为珍稀的可替代资源。为寻找新的抗菌类化合物及开展昆虫天然产物化学的研究,本文对8种昆虫提取物进行了抗菌活性的筛选和评价。研究采用了圆形纸片扩散法,以相应抗生素作为阳性对照,对昆虫70%甲醇提取物进行抗菌活性测定。结果显示,除土鳖虫外,其余7中昆虫提取物均具有较强的抗革兰阳性菌或(和)革兰阴性菌的活性。并且文中使用的溶剂两段提取方法,为以后的昆虫次生代谢物的研究奠定了技术基础。该研究将为抗生素新药先导化合物的发现和拓展昆虫化学研究方向提供新的思路。     

Structure‐based drug design and in vitro testing reveal new inhibitors of enoyl‐acyl carrier protein reductases

The need for new antibacterial agents is increasingly becoming of great importance as bacterial resistance to current drugs is quickly spreading. Enoyl‐acyl carrier protein reductases (FabI) are important enzymes for fatty acid biosynthesis in bacteria and other micro‐organisms. In this project, we conducted structure‐based virtual screening against the FabI enzyme, and accordingly, 37 compounds were selected for experimental testing. Interestingly, five compounds were able to demonstrate antimicrobial effect with variable inhibition activity against various strains of bacteria and fungi. Minimum inhibitory concentrations of the active compounds were determined and showed to be in low to medium micromolar range. Subsequently, enzyme inhibition assay was carried out for our five antimicrobial hits to confirm their biological target and determine their IC₅₀ values. Three of these tested compounds exhibited inhibition activity for the FabI enzyme where our best hit MN02 had an IC₅₀ value of 7.8 μM. Furthermore, MN02 is a small bisphenolic compound that is predicted to have all required features to firmly bind with the target enzyme. To sum up, hits discovered in this work can act as a good starting point for the future development of new and potent antimicrobial agents.     

Challenges in antimicrobial drug discovery and the potential of nucleoside antibiotics

Antimicrobial resistance in hospital and community settings is growing at an alarming rate and has been attributed to such organisms as methicillin-resistant staphylococcus aureus, staphylococci with decreased susceptibility to vancomycin, vancomycin-resistant enterococci, multi-drug resistant pseudomonas spp., klebsiella spp., enterobacter spp, and acinetobacter spp., as well as Streptococcus pneumoniae with decreased susceptibility to penicillin and other antibacterials. To address the need for new therapies to combat resistant organisms, drug companies are refocusing their discovery efforts on developing novel agents with new mechanisms of action. The hope is that rapidly emerging technologies including combinatorial chemistry, high throughput screening, proteomics and microbial genomics will have a positive impact on antimicrobial drug discovery. These technologies should aid in the identification of novel drug targets and compounds with unique mechanisms of action other than those currently provided by the traditional antibiotics. Nucleosides are one class of compounds worthy of further investigation as antibacterials since some derivatives have shown moderate to good activity against specific bacterial strains. For example, 5'-peptidyl nucleoside derivatives can inhibit peptide deformylase, an enzyme essential for bacterial survival that is not vital to human cells. This review also includes a list of miscellaneous nucleosides that have been synthesized as potential antibacterials. More detailed investigations on structure, as it relates to the antimicrobial activity of the various classes of nucleosides, need to be conducted in order to maximize the potential of developing a potent nucleoside for the treatment of bacterial infections. This review begins with an introduction to terms followed by discussions regarding the general background and relevance for developing novel antimicrobial agents. Challenges facing the antimicrobial drug discovery process are discussed along with relevant drug targets. An overview of nucleoside chemistry as it relates to antimicrobial activity is presented, followed by a discussion of the evidence which supports the potential of this class of compounds to yield the novel antimicrobial therapies needed in the new millennium.     

Synthesis, evaluation and docking studies on steroidal pyrazolones as anticancer and antimicrobial agents

A series of new steroidal pyrazolones have been synthesized, characterised and evaluated for their in vitro anticancer activity. They were tested against five cancer (SW480, HepG2, A549, HeLa and HL-60) cell lines. The synthesized compounds showed high selectivity and compound 4 showed the strongest inhibitory activity against human SW480 (IC₅₀ = 11.67 μmol L^?1). In addition, the synthesized compounds were tested for their antimicrobial activity by disc diffusion assay and MIC by broth micro dilution method against Gram-positive, Gram-negative strains of bacteria as well as fungus strains and we found a correlation between the observed and predicted antimicrobial activities. Docking studies were performed to investigate the hypothetical binding mode of the target compounds. This study provided a new molecular scaffold for the further development of anticancer as well as antimicrobial agents.     

Antimicrobial activities of human beta-defensins against Bacillus species

Natural defences in the human body function to protect us from numerous environmental toxins and exposure to potential harmful biological agents. An important frontline defence is antimicrobial peptides. These peptides occur at environmental interfaces and serve to limit bacterial invasion. There has been little work comparing specific peptides as potential antimicrobial compounds. In this study, we evaluated the antimicrobial activity of peptides from the human beta-defensin (HBD) family against four species of Bacillus, chosen as models for Bacillus anthracis, a potential bioweapon. The impact of peptide concentration, sequence and protein binding was evaluated on their biological activity. The results indicated that HBD-3 was the most biologically active against Bacillus subtilis and Bacillus licheniformis, whilst HBD-2 was found to be most active against Bacillus cereus and Bacillus thuringiensis. Moreover, the antimicrobial activity of the peptides was directly related to peptide concentration and indirectly related to albumin concentration (i.e. protein binding).     

含三唑的抗微生物药物研究进展

含三唑的化合物是目前抗微生物药物研究开发中的热点领域之一。本文结合国内外文献简述了在抗菌、抗真菌、抗结核、抗病毒方面已经上市及正在进行临床试验的含三唑的药物,着重强调了含三唑的抗微生物药物及其构效关系的研发近况。随着研究的进一步发展,有望成功地开发出更多具有显著生物学活性的新药。     

Bacterial efflux pump inhibition

Drug efflux is recognized as a clinically relevant mechanism of antimicrobial drug resistance in selected species of bacteria. Membrane-based polypeptides belong to distinct protein superfamilies, the members of which are related by structural characteristics, mechanism of action and energy source for the transport process. These membrane-based polypeptides mediate drug efflux, and some of these proteins, the multidrug efflux proteins, are capable of extruding numerous structurally dissimilar antimicrobial agents and biocides. Inhibition of these pumps can decrease intrinsic resistance, reverse acquired resistance and reduce the emergence of mutants with higher-level target-based mutational resistance. In vitro and limited in vivo investigations have shown that combining efflux pump inhibitors with antimicrobial agents that are pump substrates can result in the recovery of clinically relevant activity of those compounds. The identification of broad-spectrum efflux pump inhibitors may reduce the need, and thus cost, of discovery and development of new antimicrobial agents that are not pump substrates.     

Electrospun nanofibers as versatile platform in antimicrobial delivery: current state and perspectives

Nanotechnology has attracted increasing interest in different aspects of biotechnology. The fabrication of electrospun nanofibers (NFs) containing antibacterial agents for antimicrobial applications has been significantly enhanced in recent years. In the current review, various electrospun NFs with antimicrobial properties were introduced and evaluated. The main focus was on the recent developments and applications of antimicrobial electrospun NFs incorporated with different antimicrobial agents, including metal nanoparticles (NPs), antibiotics, quaternized ammonium compounds, triclosan, herbal extracts, carbon nanomaterials, and antimicrobial biopolymers with inherent antimicrobial properties. The search results revealed that antimicrobial containing electrospun NFs had enhanced antimicrobial performance with various biomedical applications compared to the traditional antimicrobial materials. According to the reported results, most of the studies were of an investigative nature and were mostly based on in vitro tests. Hence, further examination on in vivo clinical performance of these antimicrobial NFs seems necessary. However, these antimicrobial NFs appear to have the potential to achieve clinical usefulness and commercial production in the near future.     

Non-fermentative Gram-negative bacteria

Over the past decade, non-fermenting Gram-negative bacteria have emerged as important opportunistic pathogens in the increasing population of patients who are immunocompromised by their disease or medical treatment. These bacteria are assisted by their ubiquitous distribution in the environment and have a propensity for multiple, intrinsic or acquired drug resistance. The infections that they cause now pose significant problems in terms of treatment and infection control, whilst the commonly observed rapid emergence of bacterial resistance to new antimicrobial compounds raises concerns regarding the clinical lifespan of these agents. Studies are urgently required to assess whether combination therapy can improve the long-term utility of new drugs in the treatment of patients infected with non-fermenters.     

Evaluation of antibacterial activity of Australian basidiomycetous macrofungi using a high-throughput 96-well plate assay

Context: The production of antimicrobial compounds by macrofungi is not unexpected because they have to compete with other organisms for survival in their natural hostile environment. Previous studies have indicated that macrofungi contain secondary metabolites with a range of pharmacological activities including antimicrobial agents.

Objective: To investigate macrofungi for antimicrobial activity due to the increasing need for new antimicrobials as a result of resistance in the bacterial community to existing treatments.

Materials and methods: Forty-seven different specimens of macrofungi were collected across Queensland, Australia. Freeze-dried fruiting bodies were sequentially extracted with three solvents: water, ethanol, and hexane. These extracts were tested against representative Gram+ve, Staphylococcus aureus and Gram?ve, Escherichia coli bacteria.

Results and discussion: Overall water and ethanol extracts were more effective against S. aureus than E. coli, whereas a small number of hexane extracts showed better results for their antimicrobial potential against E. coli at higher concentrations only. Encouraging results were found for a number of macrofungi in the genera Agaricus (Agaricaceae), Amanita (Amanitaceae), Boletus (Boletaceae), Cantharellus (Cantharellaceae), Fomitopsis (Fomitopsidaceae), Hohenbuehelia (Pleurotaceae), Lentinus (Polyporaceae), Ramaria (Gomphaceae), and Strobilomyces (Boletaceae) showing good growth inhibition of the pathogens tested.

Conclusion: The present study establishes the antimicrobial potential of a sample of Australian macrofungi that can serve as potential candidates for the development of new antibiotics.     

Targeted anti bacterial therapy

The increasing development of bacterial resistance to traditional antibiotics has reached alarming levels, thus necessitating a strong need to develop new antimicrobial agents. These new antimicrobials should possess novel modes of action and/or different cellular targets compared with the existing antibiotics. As a result, new classes of compounds designed to avoid defined resistance mechanisms are undergoing pre clinical and clinical evaluation. Microbial and phage genomic sequencing are now being used to find previously unidentified genes and their corresponding proteins. In both traditional and newly developed antibiotics, the target selectivity lies in the drug itself, in its ability to affect a mechanism that is unique to prokaryotes. As a result, a vast number of potent agents that, due to low selectivity, in addition to the pathogen also affect the eukaryote host have been excluded from use as therapeutics. Such compounds could be re-considered for clinical use if applied as part of a targeted delivery platform where the drug selectivity is replaced by target-selectivity borne by the targeting moiety. With a large number of antibodies and antibody-drug conjugates already approved or near approval as cancer therapeutics, targeted therapy is becoming increasingly attractive and additional potential targeting moieties that are non-antibody based, such as peptides, non-antibody ligand-binding proteins and even carbohydrates are receiving increasing attention. Still, targeted therapy is mostly focused on cancer, with targeted anti bacterial therapies being suggested only very recently. This review will focus in the various methods of antimicrobial targeting, by systemic and local application of targeted antimicrobial substances.