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Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a global health concern. The propensity of MRSA to form biofilms is a significant contributor to its pathogenicity. Strategies to treat biofilms often involve small molecules that disperse the biofilm into planktonic cells. Linezolid and, by extension, theoxazolidinones have been developed to treat infections caused by Gram-positive bacteria such as MRSA. However, the clinical development of these antibiotics has mainly assessed the susceptibility of planktonic cells to the drug. Previous studies evaluating the anti-biofilm activity of theoxazolidinones have mainly focused on the biofilm inhibition of Enterococcus faecalis and methicillin-sensitive Staphylococcus aureus , with only a few studies investigating the activity of oxazolidinones for eradicating established biofilms for these species. Very little is known about the ability of oxazolidinones to eradicate MRSA biofilms. In this work, five oxazolidinones were assessed against MRSA biofilms using a minimum biofilm eradication concentration (MBEC) assay. All oxazolidinones had inherent antibiofilm activity. However, only ranbezolid could completely eradicate MRSA biofilms at clinically relevant concentrations. The susceptibility of the MRSA biofilms to ranbezolid was synergistically enhanced by coadministration with the nitroxide biofilm dispersal agent C-TEMPO. We presume that ranbezolid acts as a dual warhead drug, which combines the mechanism of action of the oxazolidinones with a nitric oxide donor or cytotoxic drug.

Urinary tract infections (UTIs) are the second most common bacterial infection with high recurrence rates and can involve biofilm formation on patient catheters. Biofilms are inherently tolerant to antimicrobials, making them difficult to eradicate. Many antibiofilm agents alone do not have bactericidal activity; therefore, linking them to antibiotics is a promising antibiofilm strategy. However, many of these hybrid agents have not been tested in relevant preclinical settings, limiting their potential for clinical translation. Here, we evaluate a ciprofloxacin di-nitroxide hybrid (CDN11), previously reported to have antibiofilm activity against uropathogenic Escherichia coli (UPEC) strain UTI89 in vitro, as a potential UTI therapeutic using multiple preclinical models that reflect various aspects of UTI pathogenesis. We report improved in vitro activity over the parent drug ciprofloxacin against mature UTI89 biofilms formed inside polyethylene catheters. In bladder cell monolayers infected with UTI89, treatment with CDN11 afforded significant reduction in bacterial titers, including intracellular UPEC. Infected mouse bladders containing biofilm-like intracellular reservoirs of UPEC UTI89 showed decreased bacterial loads after ex vivo bladder treatment with CDN11. Activity for CDN11 was reported across different models of UTI, showcasing nitroxide-antibiotic hybridization as a promising antibiofilm approach. The pipeline we described here could be readily used in testing other new therapeutic compounds, fast-tracking the development of novel antibiofilm therapeutics.

The selective production of primary amines is a problem that plagues heterogeneously catalysed nitrile hydrogenation reactions. Whilst the target amine tyramine (HOC 6 H 4 CH 2 CH 2 NH 2 ) is biochemically available through the action of enzymes, synthetic routes to this species are not widely reported. Here, a heterogeneously catalysed method is proposed that utilises a Pd/C catalyst to effect the selective hydrogenation of 4-hydroxybenzyl cyanide within a three-phase reactor. The aforementioned selectivity issues are overcome by adjustment of various experimental parameters (hydrogen supply, agitation rate, temperature, use of an auxiliary agent) that result in improved catalytic performance, such that the desired tyramine salt (tyramine hydrogen sulphate) can be produced in quantitative yield. Accordingly, through consideration of the interconnectivity of hydrogenation and hydrogenolysis processes, a selective synthetic strategy is achieved with the findings suitable for extension to other substrates of this nature., Competing Interests: There are no conflicts of interest., (This journal is © The Royal Society of Chemistry.)

Remote control of complex molecular behavior and function is one key problem in modern chemistry. Using light signaling for this purpose has many advantages, however the integration of different photo processes into a wholesome yet complex system is highly challenging. Here we report an alternative approach to increase complexity of light control-simultaneous complementary photoswitching-in which spectral overlap is used as an advantage to drastically reduce the signaling needed for controlling multipart supramolecular assemblies. Two photoswitchable molecular tweezers respond to the same light signals with opposite changes in their binding affinities. In this way the configuration of two host tweezers and ultimately the dynamic relocation of a guest molecule can be trigged by only one signal reversibly in the same solution. This approach should provide a powerful tool for the construction of sophisticated, integrated, and multi-responsive smart molecular systems in any application driven field of chemistry.