Synthesis and antibacterial activity of O-substituted nocathiacin I derivatives

The synthesis and antibacterial activity of a series of new nocathiacin I derivatives (1-12) containing polar water solubilizing groups is described. Most of these compounds exhibited potent antibacterial activity and have improved water solubility. In addition, compounds 5, 7-9 also exhibited potent in vivo activity.     

Addition and omission analogs of the 13-residue antibacterial and hemolytic peptide PKLLKTFLSKWIG: structural preferences, model membrane binding and biological activities.

The consequences of selective addition or deletion of polar amino acids in a 13-residue antibacterial peptide PKLLKTFLSKWIG on structure, membrane binding and biological activities have been investigated. The variants generated are (a) S and T residues replaced by K, (b) S and T residues deleted individually and together, (c) introduction of two additional K and (d) deletion of L and L with T. In the aqueous environment all the peptides were unordered. In trifluoroethanol, the spectra of peptides belonging to groups (a-c) suggest distorted helical conformation. Peptides in group (d) appear to adopt beta-sheet conformation. The peptides bind to zwitterionic and negatively charged lipid vesicles, although to different extents. With the exception of peptides in group (d), all the other peptides exhibited comparable antibacterial activity against Escherichia coli and Staphylococcus aureus. However, the changes made in the peptides in groups (a-c) resulted in reduction of hemolytic activity compared to the parent peptide. Extent of binding to lipid vesicles composed of phosphatidylcholine and cholesterol appears to correlate with hemolytic activity. It appears that polar and charged residues play a major role in modulating the biological activities of the 13-residue peptide PKLLKTFLSKWIG. The 11-residue peptide-like PKLLKFLKWIG has selective antibacterial activity. Thus, by judicious engineering it should be possible to generate short peptides with selective antibacterial activity.     

黄粉虫抗菌肽Tenecin蛋白的纯化及其抑菌活性研究

目的 纯化黄粉虫抗菌肽Tenecin蛋白,并检测其抑菌活性.方法用1 mmol/L IPTG大量诱导表达Tenecin蛋白,纯化后检测其抑菌活性,包括金黄色葡萄球菌（Staphylococcus aureus）ATCC 29213,大肠埃希菌（Escherichia coli）ATCC 25922,白色念珠菌（Candida albicans）ATCC 10231和痢疾志贺氏菌（Shigella dysenteriae）CMCC 51252等4种标准菌.结果 SDS-PAGE电泳检测表明已获得纯化的Tenecin蛋白;体外抑菌试验结果表明,浓度为120、60、30、15 μg/ml的Tenecin与4种标准菌共培养18 h后,对金黄色葡萄球菌的抑制作用最强,而对白色念珠菌的抑制作用最弱.对同一菌种而言,浓度为60和30 μg/ml两组间无统计学意义（P＞0.05）,而其他各浓度的组间均有显著性差异（P＜0.01）;对同一浓度的Tenecin而言,其对白色念珠菌和痢疾志贺氏菌的抑菌效果组间无统计学意义（P＞0.05）,其余各组之间均有显著性差异（P＜0.01）.结论 获得的Tenecin蛋白可明显抑制病原菌,为进一步研究其抑菌机理和后期研发奠定了基础.     

The role of tryptophan in the antibacterial activity of a 15-residue bovine lactoferricin peptide.

Bovine lactoferricin is a 25-residue antibacterial peptide isolated after gastric cleavage of the iron transporting protein lactoferrin. A 15-residue fragment, FKCRRWQWRMKKLGA of this peptide sustains most of the antibacterial activity. In this truncated sequence, the two Trp residues are found to be essential for antibacterial activity. The anchoring properties of Trp, as have been observed in membrane proteins, are believed to be important for the interaction of Trp containing antibacterial peptides with bacterial cell membranes. We have investigated the molecular properties which make Trp important for the antibacterial activity of the 15-residue peptide by replacing Trp with natural and unnatural aromatic amino acids. This series of peptides was tested for antibacterial activity against Echerichia coli and Staphylococcus aureus. We found that neither the hydrogen bonding ability nor the amphipathicity of the indole system are essential properties for the effect of Trp on the antibacterial activity of the peptides. Replacement of Trp with residues containing aromatic hydrocarbon side chains gave the most active peptides. We propose that aromatic hydrocarbon residues are able to position themselves deeper into the bacterial cell membrane, making the peptide more efficient in disrupting the bacterial cell membrane. From our results the size, shape and aromatic character of Trp seem to be the most important features for the activity of this class of Trp containing antibacterial peptides.     

Solution structure of termite-derived antimicrobial peptide,spinigerin, as determined in SDS micelle by NMR spectroscopy

Spinigerin is a linear antibacterial peptide derived from a termite insect. It consists of 25 amino acids and is devoid of cysteines. Spinigerin displays good lytic activities against Gram-positive and Gram-negative bacteria, but has no hemolytic activities against human erythrocytes. In this study, we present a three-dimensional solution structure of spinigerin in SDS micelles. According to CD data spinigerin has an alpha-helical conformation in the presence of TFE, DPC micelles, and SDS micelles. The three-dimensional structure of spinigerin as determined by NMR spectroscopy contains a stable alpha-helix from Lys4 to Thr23. Spinigerin (4-21), an 18-residue fragment from Lys4 to Leu21, contains a similar content of alpha-helical structure compared to native spinigerin and was found to retain antibacterial activity, too. Therefore, this alpha-helical structure and the strong electrostatic attraction between four Lys and three Arg residues in spinigerin and the negatively charged polar head groups of the phospholipids on the membrane surface play important roles in disrupting membrane and subsequent cell death.     

Structure-activity relationships of bioisosteres of a carboxylic acid in a novel class of bacterial translation inhibitors

The discovery and initial optimization of a novel anthranilic acid derived class of antibacterial agents which suffered from extensive protein binding has been previously reported. The structure-activity relationships around the carboxylic acid substituent are described herein. This acid was replaced by several alternative functional groups in attempts to retain bioactivity while reducing protein binding. Only groups with an acidic proton retained activity, and analogs containing those groups maintained the protein binding inherent to this class of antibacterial agents.     

Synthesis,Fungistatic, Protistocidal,and Antibacterial Activity of 1-(3-Amino-2-Hydroxypropyl)Indoles

A series of new indole derivatives containing the 3-amino-2-hydroxypropyl group at the nitrogen atom has been synthesized by the ring-opening of the oxirane cycle of 1-oxiranylmethylindoles. Their antibacterial, fungicidal, and protistocidal activities have been studied. Most of the synthesized compounds have been shown to exhibit a high protistocidal activity that several times exceeds that of the reference drug, baikoks (toltrazuril).     

Discovery and in vivo evaluation of alcohol-containing benzothiazoles as potent dual-targeting bacterial DNA supercoiling inhibitors

A series of dual-targeting, alcohol-containing benzothiazoles has been identified with superior antibacterial activity and drug-like properties. Early lead benzothiazoles containing carboxylic acid moieties showed efficacy in a well-established in vivo model, but inferior drug-like properties demanded modifications of functionality capable of demonstrating superior efficacy. Eliminating the acid group in favor of hydrophilic alcohol moieties at C⁵, as well as incorporating solubilizing groups at the C⁷ position of the core ring provided potent, broad-spectrum Gram-positive antibacterial activity, lower protein binding, and markedly improved efficacy in vivo.     

Synthesis and Study of Biological Activity of Sulfamic Polysaccharide Derivatives

New water-soluble derivatives of starch, pectin, and Na-CMC containing the sulfamic groups have been obtained by the reaction of sulfamic acid with dialdehyde polysaccharide derivatives. The structure and composition of the resulting compounds have been studied by IR spectroscopy, elemental (nitrogen and sulfur) analysis, and X-ray diffraction. The sulfamic derivatives of starch, pectin, and Na-CMC with a different content of the sulfamic groups have been obtained by varying the ratio of sulfamic acid to the dialdehyde polysaccharide derivatives. The optimal–СНО: NH₂SO₃H ratio was found to be 1: 2.5. The interaction rate of sulfamic acid with the dialdehyde derivatives of starch, pectin, and Na-CMC has been evaluated. The antibacterial and antifungal effects of sodium salts of the sulfamic starch, pectin, and Na-CMC derivatives against Gram-positive and Gram-negative bacteria and fungi have been studied at different concentrations (10, 25, 50 mg/mL) by the disk diffusion method. The synthesized compounds have not been found to exhibit antifungal activity against Candida albicans. Nevertheless, they have been shown to have the antibacterial activity against Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Proteus vulgaris, Streptococcus faecalis, Streptococcus pyogenes, and Streptococcus faecalis at the concentration of 50 mg/mL. The concentration dependence of antibacterial action of sodium salts of the starch, pectin, and Na-CMC sulfamic derivatives has been demonstrated. The antibacterial activity of the drugs has been found to directly depend on the content of the sulfamic groups in polysaccharides. The results on the acute toxicity of the sulfamic polysaccharide derivatives have shown that these compounds can be attributed to low-toxicity substances of Class V.     

Soil Bacteria are Differentially Affected by the Resin of the Medicinal Plant Pseudognaphalium vira vira and Its Main Component Kaurenoic Acid

The diterpenoid kaurenoic acid is the main component of the resin from the medicinal plant Pseudognaphalium vira vira. As some diterpenoids have antimicrobial properties, the effect of this resin and the kaurenoic acid on soil bacteria was studied. The resin of P. vira vira and purified kaurenoic acid were two to four times more effective as antibacterial agents with Gram-positive than with Gram-negative soil isolates. The chemical stability of kaurenoic acid and the antibacterial activity of both the resin and the diterpenoid were studied in microcosms containing plant-associated soil. After 15 days of incubation, the diterpenoid was stable, as determined by ¹H nuclear magnetic resonance and thin-layer chromatography, and soil extracts still exhibited antibacterial activity. However, after 30 days of incubation, loss of antibacterial activity of soil extracts correlated with removal or chemical modification of kaurenoic acid. The effect of the resin or this diterpenoid on the soil bacteria community was analyzed by the terminal restriction fragment length polymorphisms technique. After 15 days of incubation, the resin and the pure compound caused significant changes in the soil bacterial community. The relative abundance of specific bacterial groups was differentially affected by the resin components, being the effects with the resin stronger than with the kaurenoic acid. After 30 days of incubation, these changes mostly reverted. These results indicate that a plant resin containing diterpenoid compounds plays a significant role controlling specific groups of microorganisms in the soil associated with the plant.     

Effect of aryl ring fluorination on the antibacterial properties of C4 aryl-substituted N-methylthio beta-lactams

4-Aryl-substituted N-thiolated beta-lactams are a new family of antibacterial agents possessing unique structure-activity profiles and a mode of action. Unlike traditional beta-lactam antibiotics, which require highly polar enzyme-binding groups, these lactams bear hydrophobic groups on their side chains. In this study, we examine the effect that increasing hydrophobicity, through fluorine substitution in the C(4) aryl ring, has on the antibacterial properties.     

Preparation and characterization of durable antibacterial cellulose biomaterials modified with triazine derivatives

Cellulose fabric was chemically modified with the triazine derivatives containing the multi-cationic benzyl groups. The novel durable antibacterial cellulose biomaterial containing the multi-cationic benzyl groups was prepared. The chemical structure and thermal property of the antibacterial cellulose biomaterial were investigated with FT-IR spectra, nitrogen content analysis, and differential scanning calorimetry (DSC). The results show that the thermal stability of the novel antibacterial cellulose was slightly decreased. Physical properties of the novel antibacterial cellulose had not significant change. The novel antibacterial cellulose imparted excellent durable antibacterial properties.     

Structure-activity relationships of the peptide deformylase inhibitor BB-3497: modification of the metal binding group

A series of analogues of the potent peptide deformylase (PDF) inhibitor BB-3497 containing alternative metal binding groups was synthesised. Enzyme inhibition and antibacterial activity data for these compounds revealed that the bidentate hydroxamic acid and N-formyl hydroxylamine structural motifs represent the optimum chelating groups on the pseudopeptidic BB-3497 backbone.     

Mode of action of iturin A, an antibiotic isolated from Bacillus subtilis, on Micrococcus luteus.

Iturin A has an antibacterial activity on M. luteus which is strongly reduced in presence of MgCl₂. Iturin A lyses M. luteus protoplast, this lysis is enhanced by EDTA and inhibited by MgCl₂. These results suggest an action of iturin A on cytoplasmic membrane with interactions of both lipophilic and polypeptidic moieties of the antibiotic, respectively with membrane lipids and membrane polar components. Polar interactions involve the participation of mineral ions as magnesium ions have a strong inhibition effect on the activity of iturin A. The effect of iturin A on the incorporation of radio-active thymidine, uracil, isoleucine and alanine seems unspecific and is probably a consequence of the primary action on cytoplasmic membrane.     

Polyelectrolyte complexes between (cross-linked) N-carboxyethylchitosan and (quaternized) poly[2-(dimethylamino)ethyl methacrylate]: preparation, characterization, and antibacterial properties

Novel polyelectrolyte complexes (PECs) between N-carboxyethylchitosan (CECh) and well-defined (quaternized) poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA) have been obtained. The modification of chitosan into CECh allows the preparation of PECs in a pH range in which chitosan cannot form complexes. The CECh/PDMAEMA complex is formed in a narrow pH range around 7. The quaternization of the tertiary amino groups of PDMAEMA enables complex formation with CECh both in neutral and in alkaline medium. Cross-linked CECh is also capable of forming complexes with (quaternized) PDMAEMA. The antibacterial activity of (cross-linked) CECh, (quaternized) PDMAEMA, and their complexes against Escherichia coli has been evaluated. In contrast to (quaternized) PDMAEMA, (cross-linked) CECh exhibits no antibacterial activity. The complex formation between cross-linked CECh and (quaternized) PDMAEMA results in a loss of the inherent antibacterial activity of the latter in neutral medium. In acidic medium, the complexes exhibit strong antibacterial activity due to complex disintegration and release of (quaternized) PDMAEMA.     

Preparation, characterization and antimicrobial activity of a bio-composite scaffold containing chitosan/nano-hydroxyapatite/nano-silver for bone tissue engineering

In this study, a bio-composite scaffold containing chitosan/nano-hydroxyapatite/nano-silver particles (CS/nHAp/nAg) was developed by freeze drying technique, followed by introduction of silver ions in controlled amount through reduction phenomenon by functional groups of chitosan. The scaffolds were characterized using SEM, FT-IR, XRD, swelling, and biodegradation studies. The testing of the prepared scaffolds with Gram-positive and Gram-negative bacterial strains showed antibacterial activity. The scaffold materials were also found to be non-toxic to rat osteoprogenitor cells and human osteosarcoma cell line. Thus, these results suggested that CS/nHAp/nAg bio-composite scaffolds have the potential in controlling implant associated bacterial infection during reconstructive surgery of bone.     

油溶纳米蜂胶液联合两种根充糊剂对感染根管常见菌的体外抑菌性研究

目的探讨蜂胶类根充糊剂对感染根管常见菌的体外抑菌作用。方法选择感染根管的6种常见菌为实验菌种,琼脂扩散法观察蜂胶类根充糊剂的抗微生物作用;建立体外根管粪肠球菌感染模型,评价蜂胶类根充糊剂在离体牙根管内的抗粪肠球菌作用。结果蜂胶类根充糊剂对实验的各种细菌均具有抑菌作用,除油溶纳米蜂胶氢氧化钙甘油糊剂对粪肠球菌和具核梭杆菌的抑菌作用小于对照组外,其他实验组与对照组相比均增强了(P0.05或P0.01)或并未减弱(P0.05)原始糊剂的抑菌效果,糊剂中水溶蜂胶加入后短期内的抑菌作用优于油溶纳米蜂胶。结论蜂胶类根充糊剂对感染根管常见菌具有良好的抑菌效果,将其用作根管充填的材料具有一定的应用前景。     

Antibacterial activities in various tissues of the horse mussel, Modiolus modiolus

A search for antibacterial activity in different organs/tissues of the horse mussel, Modiolus modiolus, was conducted. Dried samples were extracted with 60% (v/v) acetonitrile, containing 0.1% (v/v) trifluoroacetic acid. Due to high salt content, two liquid phases were obtained; an acetonitrile-rich phase (ACN extract) and an aqueous phase. The aqueous phase was further subjected to solid phase extraction (SPE). Eluates from SPE and ACN extracts were tested for antibacterial, lysozyme, and toxic activity. Antibacterial activity was demonstrated in extracts from several tissues, including plasma, haemocytes, labial palps, byssus, mantle, and gills. Some of the extracts were sensitive to proteinase K treatment, indicating antibacterial peptides and/or proteins. Lysozyme-like activity and toxic activity against Artemia salina nauplii was detected in fractions from the gills, mantle, muscle, and haemocytes. Results from this study indicate that M. modiolus is a promising source for identifying novel drug lead compounds.     

Synthesis,antibacterial and anticancer activity,and docking study of aminoguanidines containing an alkynyl moiety

Abstract

Two series of aminoguanidines containing an alkynyl moiety were designed, synthesised, and screened for antibacterial and anticancer activities. Generally, the series 3a–3j with a 1,2-diphenylethyne exhibited better antibacterial activity than the other series (6a–6k) holding 1,4-diphenylbuta-1,3-diyne moiety antibacterial activity. Most compounds in series 3a–3j showed potent growth inhibition against the tested bacterial strains, with minimum inhibitory concentration (MIC) values in the range 0.25–8?µg/mL. Compound 3g demonstrated rapid and persistent bactericidal activity at 2?×?MIC. The resistance study revealed that resistance of the tested bacteria towards 3g is not easily developed. Molecular docking studies revealed that compounds 3g and 6e bind strongly to the LpxC and FabH enzymes. Moreover, excellent activity of selected compounds against the growth of cancer cell lines A549 and SGC7901 was also observed, with IC₅₀ values in the range 0.30–4.57?µg/mL. These findings indicate that compounds containing the aminoguanidine moiety are promising candidates for the development of new antibacterial and anticancer agents.     

Bioactivity,Chemical Profiling,and 16S rRNA-Based Phylogeny of <Emphasis Type="BoldItalic">Pseudoalteromonas</Emphasis> Strains Collected on a Global Research Cruise

One hundred one antibacterial Pseudoalteromonas strains that inhibited growth of a Vibrio anguillarum test strain were collected on a global research cruise (Galathea 3), and 51 of the strains repeatedly demonstrated antibacterial activity. Here, we profile secondary metabolites of these strains to determine if particular compounds serve as strain or species markers and to determine if the secondary metabolite profile of one strain represents the bioactivity of the entire species. 16S rRNA gene similarity divided the strains into two primary groups: One group (51 strains) consisted of bacteria which retained antibacterial activity, 48 of which were pigmented, and another group (50 strains) of bacteria which lost antibacterial activity upon sub-culturing, two of which were pigmented. The group that retained antibacterial activity consisted of six clusters in which strains were identified as Pseudoalteromonas luteoviolacea, Pseudoalteromonas aurantia, Pseudoalteromonas phenolica, Pseudoalteromonas ruthenica, Pseudoalteromonas rubra, and Pseudoalteromonas piscicida. HPLC-UV/VIS analyses identified key peaks, such as violacein in P. luteoviolacea. Some compounds, such as a novel bromoalterochromide, were detected in several species. HPLC-UV/VIS detected systematic intra-species differences for some groups, and testing several strains of a species was required to determine these differences. The majority of non-antibacterial, non-pigmented strains were identified as Pseudoalteromonas agarivorans, and HPLC-UV/VIS did not further differentiate this group. Pseudoalteromonas retaining antibacterial were more likely to originate from biotic or abiotic surfaces in contrast to planktonic strains. Hence, the pigmented, antibacterial Pseudoalteromonas have a niche specificity, and sampling from marine biofilm environments is a strategy for isolating novel marine bacteria that produce antibacterial compounds.