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Background Bacterial biofilm formation is a complicating factor in the antimicrobial treatment of bacterial infections. Objectives In this study, we assessed the impact of a novel hydrogel with the active antimicrobial compound JBC 1847 on eradication of preformed biofilms of Staphylococcus epidermidis, Cutibacterium acnes and MRSA in vitro, and evaluated the in vivo efficacy of MRSA wound treatment. Methods Biofilms were exposed to JBC 1847 for 24 h and subsequently the treatments were neutralized and surviving biofilm-associated bacteria recovered and enumerated. The efficacy of the hydrogel on post-treatment load of MRSA was determined in a murine model of MRSA wound infection, and skin samples of the infected mice were examined histologically to evaluate the degree of healing. Results A concentration-dependent eradication of biofilm-embedded bacteria by JBC 1847 was observed for all three pathogens, and the hydrogel caused a greater than four log reduction of cfu in all cases. In the mouse model, treatment with the hydrogel significantly reduced the cfu/mL of MRSA compared with treatment of MRSA-infected wounds with pure hydrogel. Histopathological analysis of the wounds showed that the JBC 1847 treatment group had a lower grade of inflammation, a higher mean score of re-epithelization and higher mean scores of parameters assessing the maturity of the newly formed epidermis, compared with both the fusidic acid 2% and vehicle treatment groups. Conclusions The novel hydrogel shows promising results as a candidate for future wound treatment, likely to be highly effective even in the case of biofilm-complicating infected wounds.

The emergence of multidrug-resistant bacteria constitutes a significant public health issue worldwide. Consequently, there is an urgent clinical need for novel treatment solutions. It has been shown in vitro that phenothiazines can act as adjuvants to antibiotics whereby the minimum inhibitory concentration (MIC) of the antibiotic is decreased. However, phenothiazines do not perform well in vivo, most likely because they can permeate the blood-brain (BBB) barrier and cause severe side-effects to the central nervous system. Therefore, the aim of this study was to synthesize a promazine derivate that would not cross the BBB but retain its properties as antimicrobial helper compound. Surprisingly, in vitro studies showed that the novel compound, JBC 1847 exhibited highly increased antimicrobial activity against eight Gram-positive pathogens (MIC, 0.5–2 mg/L), whereas a disc diffusion assay indicated that the properties as an adjuvant were lost. JBC 1847 showed significant (P < 0.0001) activity against a Staphylococcus aureus strain compared with the vehicle, in an in vivo wound infection model. However, both in vitro and in silico analyses showed that JBC 1847 possesses strong affinity for human plasma proteins and an Ames test showed that generally, it is a non-mutagenic compound. Finally, in silico predictions suggested that the compound was not prone to pass the BBB and had a suitable permeability to the skin. In conclusion, JBC 1847 is therefore suggested to hold potential as a novel topical agent for the clinical treatment of S. aureus skin and soft tissue infections, but pharmacokinetics and pharmacodynamics need to be further investigated.

Infections caused by bacteria resistant to antibiotics are an increasing problem. Multivalent antibiotics could be a solution. In the present study, a covalent conjugate between Ciprofloxacin and a G0-PAMAM dendrimer has been synthesized and tested against clinically relevant Gram-positive and Gram-negative bacteria. The conjugate has antimicrobial activity and there is a positive dendritic effect compared to Ciprofloxacin itself.

The simple reduction of a number of alkenes and alkynes was performed with a typical reaction time of 20 min using a copper-cobalt catalytic system. The reduction did not cleave benzyl protecting groups which are usually vulnerable to catalytic hydrogenation reactions. The catalyst can be prepared in situ by reduction of the inexpensive precursor salts CuSO4 and CoCl2 with NaBH4. Sodium borohydride was also used as an easily handled hydrogen source for the catalytic reductions. No pressure, heating or inert atmosphere is required and purification/catalyst removal is achieved using extraction procedures, making this approach simple and efficient.

Sertraline, an antidepressive drug, has been reported to inhibit general bacterial efflux pumps. In the present study, we report for the first time a synergistic effect of sertraline and tetracycline in a TetA-encoded tetracycline-resistant strain of Escherichia coli. Synergy between sertraline and tetracycline in an E. coli strain with TetA-mediated tetracycline resistance (E. coli APEC-O2) was assessed by the MIC and checkerboard assays. The global transcriptome of E. coli APEC-O2 exposed to MIC concentrations of sertraline and/or tetracycline was analyzed to elucidate the interaction mechanism between sertraline and tetracycline. The fractional inhibitory concentration index for tetracycline and sertraline in E. coli APEC-O2 was 0.5. In addition, in the presence of MIC of sertraline, the sensitivity of E. coli APEC-O2 to tetracycline could be restored according to clinical standards (from 64 to 4 mg l â '1). RNA data suggest changes in respiration that is likely to decrease intracellular pH and thereby the proton-motive force, which provides the energy for the tetracycline efflux pump. Furthermore, sertraline and tetracycline may induce a change from oxidation to fermentation in the E.coli, which further decreases pH, resulting in cell death. This study shows that sertraline interacts with tetracycline in a synergistic and AcrAB-TolC pump-independent manner. The combinational treatment was further shown to induce many changes in the global transcriptome, including altered tetA and tetR expression. The results indicate that sertraline may be used as a helper compound with the aim to reverse tetracycline resistance encoded by tetA.

The therapeutic effect of indomethacin, a water-insoluble non-steroidal anti-inflammatory drug, requires its efficient transport through cellular membranes and accumulation inside the target cells. The application of dendritic polymers has been proposed for the improvement of the drug's solubility and intracellular delivery. In this study we evaluated the anti-inflammatory potential of novel, highly-biocompatible 4-carbomethoxypyrrolidone-coated PAMAM dendrimers loaded with indomethacin. Our results indicate that complexation with dendrimers do not hamper the inhibitory action of indomethacin towards cyclooxygenases. Drug-dendrimer formulations exhibited improved anti-inflammatory activity in in vitro-cultured cellular models, showing enhanced inhibition of prostaglandin secretion and significantly decreased expression of NF-κB marker genes compared to free drug.

The application of dendrimers for biological and medical purposes is highly dependent on the type of surface group in relation to cytotoxicity. Since amine terminated PAMAM dendrimers have been shown to have toxic properties and thereby limited applications in the medical field, the discovery of a new nontoxic surface coating is of great interest. In the present work, amine terminated DAB-PAMAM dendrimers from generation zero to four have been coated with statistical surface functionalization giving a dendrimer surface consisting of an approximately 1:1 mixture of zwitterionic phosphoryl choline hexanamide and 6-((6-hydroxyhexanoyl)oxy)hexanamide. The cytotoxic properties of generation two to four were tested on three different human cancer cell lines, SKBR3 human breast cancer cells, HeLa human cervical cancer cells, and Hep G2 human hepatocellular liver carcinoma cells and compared to the toxicity of amine terminated PAMAM dendrimers. In addition to lower cytotoxicity than observed for amine terminated dendrimers, the coated dendrimers showed minor cytotoxicity against all three human cell lines, negligible influence on ROS generation and mitochondrial membrane potential. These observations support the conclusion that the analyzed group of phosphorylcholine dendrimers may be suitable for medical applications.

Thioridazine hydrochloride (HCl) has been suggested as a promising antimicrobial helper compound for the treatment of infections with antimicrobial-resistant bacteria. Unfortunately, the therapeutic concentration of thioridazine HCl is generally higher than what can be tolerated clinically, in part due to its toxic side effects on the central nervous system. Therefore, we aimed to synthesize a less toxic thioridazine derivative that would still retain its properties as a helper compound. This resulted in a compound designated 1-methyl-2-(2-(2-(methylthio)-10H-phenothiazin-10-yl)ethyl)-1-pentylpiperidin-1-ium bromide (abbreviated T5), which exhibited low blood&ndash, brain barrier permeability. The lowest minimal inhibitory concentration (MIC) against Staphylococcus aureus exposed to the novel compound was reduced 32-fold compared to thioridazine HCl (from 32 &micro, g/mL to 1 &micro, g/mL). The MIC values for T5 against five Gram-positive pathogens ranged from 1 &micro, g/mL to 8 &micro, g/mL. In contrast to thioridazine HCl, T5 does not act synergistically with oxacillin. In silico predictive structure analysis of T5 suggests that an acceptably low toxicity and lack of induced cytotoxicity was demonstrated by a lactate dehydrogenase assay. Conclusively, T5 is suggested as a novel antimicrobial agent against Gram-positive bacteria. However, future pharmacokinetic and pharmacodynamic studies are needed to clarify the clinical potential of this novel discovery.

COX-2 inhibitors such as nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common treatment for chronic inflammatory diseases like arthritis and atherosclerosis. However, they are associated with severe side effects such as cardiovascular events or stomach bleeding, due to coinhibition of other enzymes (COX1) and off-target accumulation. PAMAM dendrimers can solubilize lipophilic drugs and increase their circulation time; furthermore, PAMAM dendrimers seem to have some accumulation in inflammatory sides. Three different generations of 4-carbomethoxypyrrolidone (Pyr) surface-modified PAMAM dendrimers were complexed with the NSAID drug indomethacin, and their in-solution thermodynamic profiles were studied by means of NMR experiments. The binding stoichiometry was found dependent on solvent system and dendrimer generation. Larger dendrimers (G3-Pyr) were found to bind indomethacin through entropy driven binding mode, while G1-Pyr and G2-Pyr expressed an enthalpy driven complex formation, which means that the binding constants have a generational temperature dependency. G1/2-Pyr showed reduced binding with increasing temperature, which could be important for drug release at inflammatory sites, which have, in general, elevated temperatures. In vitro studies elucidated that the indomethacin drug remained its activity when delivered as a dendrimer-indomethacin complex. A slight reduction in toxicity profile was noticed for G2/G3-Pyr-indomethacin dendrimers. Both free indomethacin and dendrimer-indomethacin complex inhibited a variety of pro-inflammatory cytokines in LPS treated cells. However, only the indo-dendrimer complexes showed a significant reduction of IL-1β in LPS-treated THP-1 cells, which was not present in the control with free indomethacin.