3D QSAR studies of N-4-arylacryloylpiperazin-1-yl-phenyl-oxazolidinones: A novel class of antibacterial agents

Three-dimensional QSAR studies for N-4-arylacryloylpiperazin-1-yl-phenyl-oxazolidinones were conducted using TSAR 3.3. The in vitro activities (MICs) of the compounds against Staphylococcus aureus ATCC 25923 exhibited a strong correlation with the prediction made by the model developed in the present study.

Design, synthesis, and application of novel triclosan prodrugs as potential antimalarial and antibacterial agents

A number of new triclosan-conjugated analogs bearing biodegradable ester linkage have been synthesized, characterized and evaluated for their antimalarial and antibacterial activities. Many of these compounds exhibit good inhibition against Plasmodium falciparum and Escherichia coli. Among them tertiary amine containing triclosan-conjugated prodrug (5) inhibited both P. falciparum (IC50; 0.62 μM) and E. coli (IC50; 0.26 μM) at lower concentrations as compared to triclosan. Owing to the presence of a cleavable ester moiety, these new prodrugs are hydrolyzed under physiological conditions and parent molecule, triclosan, is released. Further, introduction of tertiary/quaternary functionality increases their cellular uptake. These properties impart them with higher potency to their antimalarial as well as antibacterial activities. The best compound among them 5 shows close to four-fold enhanced activities against P. falciparum and E. coli cultures as compared to triclosan.

Application of flow cytometry for the determination of minimal inhibitory concentration of several antibacterial agents on Mycoplasma hyopneumoniae

P. Assun??o, N.T. Antunes, R.S. Rosales, C. Poveda, C. de la Fe, J.B. Poveda and H.M. Davey (2007). Application of flow cytometry for the determination of minimal inhibitory concentration of several antibacterial agents on Mycoplasma hyopneumoniae. Journal of Applied Microbiology, 102(4), 1132-1137. Sponsorship: Gobierno de Canarias (IDT-LP-04/016) RAE2008

Synthesis and biological analysis of novel glycoside derivatives of L-AEP, as targeted antibacterial agents

To develop targeted methods for treating bacterial infections, the feasibility of using glycoside derivatives of the antibacterial compound L-R-aminoethylphosphonic acid (L-AEP) has been investigated. These derivatives are hypothesized to be taken up by bacterial cells via carbohydrate uptake mechanisms, and then hydrolysed in situ by bacterial borne glycosidase enzymes, to selectively afford L-AEP. Therefore the synthesis and analysis of ten glycoside derivatives of L-AEP, for selective targeting of specific bacteria, is reported. The ability of these derivatives to inhibit the growth of a panel of Gram-negative bacteria in two different media is discussed. β-Glycosides (12a) and (12b) that contained L-AEP linked to glucose or galactose via a carbamate linkage inhibited growth of a range of organisms with the best MICs being <0.75 mg/ml; for most species the inhibition was closely related to the hydrolysis of the equivalent chromogenic glycosides. This suggests that for (12a) and (12b), release of L-AEP was indeed dependent upon the presence of the respective glycosidase enzyme.

Synthesis and evaluation of cationic norbornanes as peptidomimetic antibacterial agents

A series of structurally amphiphilic biscationic norbornanes have been synthesised as rigidified, low molecular weight peptidomimetics of cationic antimicrobial peptides. A variety of charged hydrophilic functionalities were attached to the norbornane scaffold including aminium, guanidinium, imidazolium and pyridinium moieties. Additionally, a range of hydrophobic groups of differing sizes were incorporated through an acetal linkage. The compounds were evaluated for antibacterial activity against both Gram-negative and Gram-positive bacteria. Activity was observed across the series; the most potent of which exhibited an MIC's ≤ 1 μg mL(-1) against Streptococcus pneumoniae, Enterococcus faecalis and several strains of Staphylococcus aureus, including multi-resistant methicillin resistant (mMRSA), glycopeptide-intermediate (GISA) and vancomycin-intermediate (VISA) S. aureus.

Norbornane-based peptidomimetics as antibacterial agents

 A library of norbornane-based peptide mimetics have been synthesised and shown to exhibit antibacterial activity against a range of troublesome Gram-positive and Gram-negative bacterial pathogens.

Effects of Antibacterial Agents on Dental Pulps of Monkeys Mechanically Exposed and Contaminated.

The purpose of this study was to compare the effectiveness of antibacterial agents and mineral trioxide aggregate in the healing of bacterial contaminated primate pulps. Study Design: The experiment required four adult male primates (Cebus opella) with 48 teeth prepared with buccal penetrartions into the pulpal tissues. The preparations (Cebus opella) with 48 teeth prepared with buccal penetrations into the exposed to cotton pellets soaked in a bacterial mixture consisting of microorganisms normally found in human pulpal abscesses obtained from the Endodontic Clinic of UNESP. Following bacterial inoculation (30 minute exposure), the pulpal tissue was immediately treated with either sterile saline, Cipro HC Otic solution (12), diluted Buckley formecresol solution (12) or Otosporin otic solution (12) for 5 minutes. After removal of the pellet, hemostasis was obtained and a ZOE base applied to the DFC treated pulps and the non-treated controls (12). After hemostasis, the other exposed pulps were covered with mineral trioxide aggregate (ProRoot). The pulpal bases were all covered with a RMGI (Fuji II LC). The tissue samples were collected at one day, two days, one week and over four weeks (34 days). Results: Following perfusion fixation, the samples were demineralized, sectioned, stained and histologically graded. After histologic analysis, presence of neutrophilic infiltrate and areas of hemorrhage with hyperemia were observed . The depth of the neutrophilic infiltrate depended on the agent or material used. The pupal tissue treated with Otic suspensions demonstrated significantly less inflammation (Kruskal Wallis non parametric analysis, H=9.595 with 1 degree of freedom; P=0.0223) than the formocresol and control groups. The hard tissue bridges formed over the exposure sites were more organized in the MTA treatment groups than in the control and ZOE groups (Kruskal Wallis non parametric analysis, H=18.291 with 1 degree of freedom; P=0.0004). Conclusions: Otic suspensions and MTA are effective in treating bacterial infected pulps and stimulate the production of a hard tissue bridge over the site of the exposure.

Long-circulating bacteriophage as antibacterial agents.

The increased prevalence of multidrug-resistant bacterial pathogens motivated us to attempt to enhance the therapeutic efficacy of bacteriophages. The therapeutic application of phages as antibacterial agents was impeded by several factors: (i) the failure to recognize the relatively narrow host range of phages; (ii) the presence of toxins in crude phage lysates; and (iii) a lack of appreciation for the capacity of mammalian host defense systems, particularly the organs of the reticuloendothelial system, to remove phage particles from the circulatory system. In our studies involving bacteremic mice, the problem of the narrow host range of phage was dealt with by using selected bacterial strains and virulent phage specific for them. Toxin levels were diminished by purifying phage preparations. To reduce phage elimination by the host defense system, we developed a serial-passage technique in mice to select for phage mutants able to remain in the circulatory system for longer periods of time. By this approach we isolated long-circulating mutants of Escherichia coli phage lambda and of Salmonella typhimurium phage P22. We demonstrated that the long-circulating lambda mutants also have greater capability as antibacterial agents than the corresponding parental strain in animals infected with lethal doses of bacteria. Comparison of the parental and mutant lambda capsid proteins revealed that the relevant mutation altered the major phage head protein E. The use of toxin-free, bacteria-specific phage strains, combined with the serial-passage technique, may provide insights for developing phage into therapeutically effective antibacterial agents.

Modes of action of antibacterial agents

This chapter describes the modes of action of the major antibiotics and synthetic agents used to treat bacterial infections. Particular attention is given to the biochemical mechanisms by which the agents interfere with biosynthetic processes and the basis for their selective antibacterial action. Interference with the biosynthesis and assembly of structural components of the bacterial cell wall provides the basis for many important groups of antibiotics, including the agents targeting steps in peptidoglycan synthesis. Other agents exploit more subtle differences between bacteria and mammalian cells in fundamental processes such as DNA, RNA and protein synthesis.

Developing an anion host for lipid A binding and antibacterial activity

New structural amphiphiles 2a and 2b bind the diphosphate lipid A anion and show potential as lead compounds for the development of novel antibacterial agents.

The origin of the antibacterial property of bamboo

Bamboo is an eco-friendly and multifunctional plant. Bamboo clothing has recently entered the textile market with a claim for its antimicrobial properties, but without scientific evidence. In this study, the antibacterial activity of plant extracts from Australian-grown bamboo (Phyllostachys pubescens) is investigated. Bamboo extracts were made using water, dimethyl sulphoxide (DMSO) and dioxane and their antibacterial properties were compared against Gram-negative bacteria, Escherichia coli. It was found that the extract made in 20% DMSO aqueous solution showed weak antibacterial activity, whereas the extract made using 90% dioxane aqueous solution exhibited strong antibacterial activity, even after 20 times dilution. The results indicate that antibacterial agents of P. pubescens are located in lignin, not in hemicellulose or other water-soluble chemical components.

Novel 1,4-substituted-1,2,3-triazoles as antitubercular agents

Tuberculosis (TB) remains a pressing unmet medical need, particularly with the emergence of multidrug-resistant and extensively drug-resistant tuberculosis. Here, a series of 1,4-substituted-1,2,3-triazoles have been synthesized and evaluated as potential antitubercular agents. These compounds were assembled via click chemistry in high crude purity and in moderate to high yield. Of the compounds tested, 12 compounds showed promising antitubercular activity with six possessing minimum inhibitory concentration (MIC) values <10 μg mL^-1, and total selectivity for Mycobacterium tuberculosis (Mtb) growth inhibition. A second set of 21 compounds bearing variations on ring C were synthesized and evaluated. This second library gave an additional six compounds displaying MIC values ≤10 μg mL^-1 and total selectivity for Mtb growth inhibition. These compounds serve as an excellent starting point for further development of antitubercular therapies.