Open Source Antibiotics: Simple Diarylimidazoles Are Potent against Methicillin-Resistant Staphylococcus aureus.

Antimicrobial resistance (AMR) is widely acknowledged as one of the most serious public health threats facing the world, yet the private sector finds it challenging to generate much-needed medicines. As an alternative discovery approach, a small array of diarylimidazoles was screened against the ESKAPE pathogens, and the results were made publicly available through the Open Source Antibiotics (OSA) consortium (https://github.com/opensourceantibiotics). Of the 18 compounds tested (at 32 µg/mL), 15 showed >90% growth inhibition activity against methicillin-resistant Staphylococcus aureus (MRSA) alone. In the subsequent hit-to-lead optimization of this chemotype, 147 new heterocyclic compounds containing the diarylimidazole and other core motifs were synthesized and tested against MRSA, and their structure-activity relationships were identified. While potent, these compounds have moderate to high intrinsic clearance and some associated toxicity. The best overall balance of parameters was found with OSA_975, a compound with good potency, good solubility, and reduced intrinsic clearance in rat hepatocytes. We have progressed toward the knowledge of the molecular target of these phenotypically active compounds, with proteomic techniques suggesting TGFBR1 is potentially involved in the mechanism of action. Further development of these compounds toward antimicrobial medicines is available to anyone under the licensing terms of the project.

Direct conjugation of distinct carbon dots as Lego-like building blocks for the assembly of versatile drug nanocarriers.

As a promising drug nanocarrier, carbon dots (CDs) have exhibited many excellent properties. However, some properties such as bone targeting and crossing the blood-brain barrier (BBB) only apply to a certain CD preparation with limited drug loading capacity. Therefore, it is significant to conjugate distinct CDs to centralize many unique properties on the novel drug nanocarrier. Considering that CDs have abundant and tunable surface functionalities, in this study, a direct conjugation was initiated between two distinct CD models, black CDs (B-CDs) and gel-like CDs (G-CDs) via an amidation reaction. As a result of conjugation at a mass ratio of 5:3 (B-CDs to G-CDs) and a two-step purification process, the conjugate, black-gel CDs (B-G CDs) (5:3) inherited functionalities from both CDs and obtained an enhanced thermostability, aqueous stability, red-shifted photoluminescence (PL) emission, and a figure-eight shape with a width and length of 3 and 6 nm, respectively. In addition, the necessity of high surface primary amine (NH2) content in the CD conjugation was highlighted by replacing G-CDs with other CDs with lower surface NH2 content. Meanwhile, the carboxyl groups (COOH) on G-CDs were not enough to trigger self-conjugation between G-CDs. Moreover, the drug loading capacity was enhanced by 54.5% from B-CDs to B-G CDs (5:3). Furthermore, when the mass ratio of B-CDs to G-CDs was decreased from 5:30, 5:100 to 5:300, the obtained nanostructures revealed a great potential of CDs as Lego-like building blocks. Also, bioimaging of zebrafish demonstrated that various B-G CDs exhibited properties of both bone targeting and crossing the BBB, which are specific properties of B-CDs and G-CDs, respectively.

Size-Dependent Photocatalytic Activity of Carbon Dots with Surface-State Determined Photoluminescence.

Carbon dots (CDs) were synthesized by a microwave-mediated method and separated by size exclusion chromatography into three different size fractions. There was no correlation of the size with photoluminescence (PL) emission wavelength, which shows that the PL mechanism is not quantum-size dependent. UV/vis absorption and diffuse reflectance spectroscopies showed that the light absorption properties as well as the band gap of the CDs changed with the size of the particle. The combination of FTIR and XPS measurements revealed the composition on the surface of each fraction. The three CDs fractions were separately used in the photocatalytic degradation of organic dyes under simulated sunlight irradiation. The catalytic activity of the as-prepared CDs was found to increase as the size of the particles decreased. Complete degradation of both rhodamine B (RhB) and methylene blue (MB) was achieved in 150 min by the 2-nm CDs. The scavenger studies showed that the holes and superoxide radicals are the main species involved in the photocatalytic degradation of the dye by the 2-nm CDs. These CDs displayed high stability in the degradation of organic dyes for multiple cycles. The 2-nm CDs displayed promising photocatalytic degradation of p-nitrophenol (PNP) . These results demonstrate for the first time the application of bare carbon dots in the degradation of environmental contaminants.