Toward the Identification of Novel Antimicrobial Agents: One-Pot Synthesis of Lipophilic Conjugates of N-Alkyl d- and l-Iminosugars

In the effort to improve the antimicrobial activity of iminosugars, we report the synthesis of lipophilic iminosugars 10a-b and 11a-b based on the one-pot conjugation of both enantiomeric forms of N-butyldeoxynojirimycin (NBDNJ) and N-nonyloxypentyldeoxynojirimycin (NPDNJ) with cholesterol and a succinic acid model linker. The conjugation reaction was tuned using the established PS-TPP/I2/ImH activating system, which provided the desired compounds in high yields (94-96%) by a one-pot procedure. The substantial increase in the lipophilicity of 10a-b and 11a-b is supposed to improve internalization within the bacterial cell, thereby potentially leading to enhanced antimicrobial properties. However, assays are currently hampered by solubility problems; therefore, alternative administration strategies will need to be devised

Steroid derivatives as potential antimicrobial agents against Staphylococcus aureus planktonic cells

In this work, the antibacterial activity of deflazacort and several of its synthetic precursors was tested against a panel of bacterial pathogens responsible for most drug-resistant infections including Staphylococcus aureus, Enterococcus spp., Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, and Enterobacter spp. The derivative of deflazacort, PYED-1 (pregnadiene-11-hydroxy-16α,17α-epoxy-3,20-dione-1) showed the best antibacterial activity in a dose-dependent way. We focused on the action of PYED-1 against S. aureus cells. PYED-1 exhibited an additive antimicrobial effect with gentamicin and oxacillin against the methicillin-resistant S. aureus isolate 00717. In addition to its antimicrobial effect, PYED-1 was found to repress the expression of several virulence factors of S. aureus, including toxins encoded by the hla (alpha-haemolysin), hlb (beta-haemolysin), lukE-D (leucotoxins E-D), and sea (staphylococcal enterotoxin A) genes, and cell surface factors (fnbB (fibronectin-binding protein B) and capC (capsule biosynthesis protein C)). The expression levels of autolysin isaA (immunodominant staphylococcal antigen) were also increased

N-nonyloxypentyl-l-deoxynojirimycin inhibits growth, biofilm formation and virulence factors expression of Staphylococcus aureus

Staphylococcus aureus is one of the major causes of hospital-and community-associated bacterial infections throughout the world, which are difficult to treat due to the rising number of drug-resistant strains. New molecules displaying potent activity against this bacterium are urgently needed. In this study, d-and l-deoxynojirimycin (DNJ) and a small library of their N-alkyl derivatives were screened against S. aureus ATCC 29213, with the aim to identify novel candidates with inhibitory potential. Among them, N-nonyloxypentyl-l-DNJ (l-NPDNJ) proved to be the most active compound against S. aureus ATCC 29213 and its clinical isolates, with the minimum inhibitory concentration (MIC) value of 128 µg/mL. l-NPDNJ also displayed an additive effect with gentamicin and oxacillin against the gentamicin-and methicillin-resistant S. aureus isolate 00717. Sub-MIC values of l-NPDNJ affected S. aureus biofilm development in a dose-dependent manner, inducing a strong reduction in biofilm biomass. Moreover, real-time reverse transcriptase PCR analysis revealed that l-NPDNJ effectively inhibited at sub-MIC values the transcription of the spa, hla, hlb and sea virulence genes, as well as the agrA and saeR response regulator genes

Dedicated versus mainstreaming approaches in local climate plans in Europe

Cities are gaining prominence committing to respond to the threat of climate change, e.g., by developing local climate plans or strategies. However, little is known regarding the approaches and processes of plan development and implementation, or the success and effectiveness of proposed measures. Mainstreaming is regarded as one approach associated with (implementation) success, but the extent of integration of local climate policies and plans in ongoing sectoral and/or development planning is unclear. This paper analyses 885 cities across the 28 European countries to create a first reference baseline on the degree of climate mainstreaming in local climate plans. This will help to compare the benefits of mainstreaming versus dedicated climate plans, looking at policy effectiveness and ultimately delivery of much needed climate change efforts at the city level. All core cities of the European Urban Audit sample were analyzed, and their local climate plans classified as dedicated or mainstreamed in other local policy initiatives. It was found that the degree of mainstreaming is low for mitigation (9% of reviewed cities; 12% of the identified plans) and somewhat higher for adaptation (10% of cities; 29% of plans). In particular horizontal mainstreaming is a major effort for local authorities; an effort that does not necessarily pay off in terms of success of action implementation. This study concludes that climate change issues in local municipalities are best tackled by either, developing a dedicated local climate plan in parallel to a mainstreamed plan or by subsequently developing first the dedicated and later a mainstreaming plan (joint or subsequent “dual track approach”). Cities that currently provide dedicated local climate plans (66% of cities for mitigation; 26% of cities for adaptation) may follow-up with a mainstreaming approach. This promises effective implementation of tangible climate actions as well as subsequent diffusion of climate issues into other local sector policies. The development of only broad sustainability or resilience strategies is seen as critical.We thank the many council representatives that supported the datacollection. Special thanks to Birgit Georgi who helped in setting up this large net work of researchers across the EU-28. We also thank the EU COST Action TU 0902 (ledbyRichardDawson) that established the core research network and the positive engagement and interaction of th emembers of this group. OH is Fellow of the Tyndall Centre for Climate Change Research and was funded by the UK EPSRC LC Transforms: Low Carbon Transitions of Fleet Operations in Metropolitan Sites Project (grant number EP/N010612/1). EKL was supported by the Ministry of Education, Youth and Sports, Czechia, within the National Sustainability Program I (NPU I) (grant number LO1415). DG ac-knowledges support by the Ministry of Education, University and Research (MIUR), Italy ("Departments of Excellence" grant L. 232/2016). HO was supported by the Ministry of Education and Research, Estonia (grantnumberIUT34-17). MO acknowledges funding from the Ministry of Economy and Competitiveness (MINECO), Spain (grant number IJCI-2016-28835). SS acknowledges that CENSE's research is partially funded by the Science Foundation, Portugal (grant number UID/AMB/04085/2019). The paper reflects only the views of the authors. The European Union, the European Environment Agency or other supporting bodies are not liable for any use that may be made of the information that is provided in this manuscript

Longitudinal performance of senescence accelerated mouse prone-strain 8 (SAMP8) mice in an olfactory-visual water maze challenge

© 2018 Lam, Takechi, Albrecht, D’Alonzo, Graneri, Hackett, Coulson, Fimognari, Nesbit and Mamo. Morris water maze (MWM) is widely used to assess cognitive deficits in pre-clinical rodent models. Latency time to reach escape platform is frequently reported, but may be confounded by deficits in visual acuity, or differences in locomotor activity. This study compared performance of Senescence Accelerated Mouse Prone-Strain 8 (SAMP8) and control Senescence Accelerated Mouse Resistant-Strain 1 (SAMR1) mice in classical MWM, relative to performance in a newly developed olfactory-visual maze testing protocol. Performance indicated as the escape time to rescue platform for classical MWM testing showed that SAMP8 mice as young as 6 weeks of age did poorly relative to age-matched SAMR1 mice. The olfactory-visual maze challenge described better discriminated SAMP8 vs. SAMR1 mice than classical MWM testing, based on latency time measures. Consideration of the distance traveled rather than latency time in the classical MWM found no treatment effects between SAMP8 and SAMR1 at 40 weeks of age and the olfactory-visual measures of performance confirmed the classical MWM findings. Longitudinal (repeat) assessment of SAMP8 and SAMR1 performance at 6, 20, 30, and 40 weeks of age in the olfactory-visual testing protocol showed no age-associated deficits in SAMP8 mice to the last age end-point indicated. Collectively, the results from this study suggest the olfactory-visual testing protocol may be advantageous compared to classical MWM as it avoids potential confounders of visual impairment in some strains of mice and indeed, may offer insight into cognitive and behavioral deficits that develop with advanced age in the widely used SAMP8 murine model

Pulmonary arterial hypertension: from the kingdom of the near-dead to multiple clinical trial meta-analyses

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326peffectiveness of trastuzumab emtansine tdm1 in patients with her2 positive advanced breast cancer abc progressing after taxane plus pertuzumab plus trastuzumab

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