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Synthetic retinoid compounds can kill both growing and persister MRSA cells by disrupting the membrane lipid bilayer, and are effective in a mouse model of chronic MRSA infection. Drugs to beat persistence Bacterial persisters are a subpopulation of cells that can survive lethal antibiotics and other stresses. They are a major challenge for antimicrobial therapy as they cannot be killed by traditional therapeutic agents. Eleftherios Mylonakis and colleagues have developed retinoid compounds that can kill both growing and persister MRSA cells by disrupting the membrane. They develop one of these compounds with an improved cytotoxicity profile, and show that it is effective in treating a mouse model of chronic MRSA infection. Further development of these antibiotics is required to improve safety margins to move the antibiotics closer to being viable clinical candidates. A challenge in the treatment of Staphylococcus aureus infections is the high prevalence of methicillin-resistant S. aureus (MRSA) strains and the formation of non-growing, dormant ‘persister’ subpopulations that exhibit high levels of tolerance to antibiotics 1 , 2 , 3 and have a role in chronic or recurrent infections 4 , 5 . As conventional antibiotics are not effective in the treatment of infections caused by such bacteria, novel antibacterial therapeutics are urgently required. Here we used a Caenorhabditis elegans –MRSA infection screen 6 to identify two synthetic retinoids, CD437 and CD1530, which kill both growing and persister MRSA cells by disrupting lipid bilayers. CD437 and CD1530 exhibit high killing rates, synergism with gentamicin, and a low probability of resistance selection. All-atom molecular dynamics simulations demonstrated that the ability of retinoids to penetrate and embed in lipid bilayers correlates with their bactericidal ability. An analogue of CD437 was found to retain anti-persister activity and show an improved cytotoxicity profile. Both CD437 and this analogue, alone or in combination with gentamicin, exhibit considerable efficacy in a mouse model of chronic MRSA infection. With further development and optimization, synthetic retinoids have the potential to become a new class of antimicrobials for the treatment of Gram-positive bacterial infections that are currently difficult to cure.

The C-type lectin receptor MelLec recognizes DHN-melanin in conidial spores of Aspergillus fumigatus and other DHN-melanized fungi, revealing an important role for this receptor in antifungal immunity in both mice and humans. Cell receptor triggers antifungal immunity Defence against fungal pathogens in mammals relies on pattern recognition receptors, which are often activated by pathogen virulence factors. One such factor is melanin, a component of the fungal cell wall. Gordon Brown and colleagues identify the melanin-sensing C-type lectin receptor (MelLec) as an endothelial cell receptor for fungal melanin. Activation of this receptor triggers a protective inflammatory response against infection by Aspergillus fungi in mice and humans. MelLec thereby has an important role in host defence against disseminated Aspergillosis . Resistance to infection is critically dependent on the ability of pattern recognition receptors to recognize microbial invasion and induce protective immune responses. One such family of receptors are the C-type lectins, which are central to antifungal immunity 1 . These receptors activate key effector mechanisms upon recognition of conserved fungal cell-wall carbohydrates. However, several other immunologically active fungal ligands have been described; these include melanin 2 , 3 , for which the mechanism of recognition is hitherto undefined. Here we identify a C-type lectin receptor, melanin-sensing C-type lectin receptor (MelLec), that has an essential role in antifungal immunity through recognition of the naphthalene-diol unit of 1,8-dihydroxynaphthalene (DHN)-melanin. MelLec recognizes melanin in conidial spores of Aspergillus fumigatus as well as in other DHN-melanized fungi. MelLec is ubiquitously expressed by CD31 + endothelial cells in mice, and is also expressed by a sub-population of these cells that co-express epithelial cell adhesion molecule and are detected only in the lung and the liver. In mouse models, MelLec was required for protection against disseminated infection with A. fumigatus . In humans, MelLec is also expressed by myeloid cells, and we identified a single nucleotide polymorphism of this receptor that negatively affected myeloid inflammatory responses and significantly increased the susceptibility of stem-cell transplant recipients to disseminated Aspergillus infections. MelLec therefore recognizes an immunologically active component commonly found on fungi and has an essential role in protective antifungal immunity in both mice and humans.

This study reports the concentrations and congener partners of polychlorinated biphenyls (PCBs) in commercially available paints. Polycyclic-type pigments containing dioxazine violet (pigment violet (PV) 23, PV37) and diketopyrrolopyrrole (PR254, PR255) were found to contain PCB-56, PCB-77, PCB-40, PCB-5, and PCB-12, and PCB-6, PCB-13, and PCB-15, respectively, as major congeners. Dioxazine violet is contaminated with by-products during synthesis from o -dichlorobenzene, which is used as a solvent during synthesis, and diketopyrrolopyrrole is contaminated with by-products during synthesis from p -chlorobenzonitrile. The concentration of PCBs in paint containing PV23 or PV37 was 0.050–29 mg/kg, and toxic equivalency (TEQ) values ranged 1.1–160 pg-TEQ/g. The concentration of PCBs in paint containing PR254 or PR255 was 0.0019–2.4 mg/kg. Naphthol AS is an azo-type pigment, and PCB-52 was detected in paint containing pigment red (PR) 9 with 2,5-dichloroaniline as its source. PCB-146, PCB-149, and PCB-153 were identified from paint containing PR112 produced from 2,4,5-trichloroaniline, as major congeners. These congeners have chlorine positions similar to aniline, indicating that these congeners are by-products obtained during the synthesis of pigments. The concentrations of PCBs in paints containing PR9 and PR112 were 0.0042–0.43 and 0.0044–3.8 mg/kg, respectively. The corresponding TEQ for PR112 was 0.0039–8.6 pg-TEQ/g.

1'-Hydroxy-4',8,8'-trimethoxy-[2,2'-binaphthalene]-1,4-dione (compound ), a secondary metabolite recently discovered in marine fungi, demonstrates promising cytotoxic and anticancer potential. However, knowledge regarding the anticancer activities and biological mechanisms of its derivatives remains limited. Herein, a series of novel naphthoquinone-naphthol derivatives were designed, synthesised, and evaluated for their anticancer activity against cancer cells of different origins. Among these, Compound , featuring an oxopropyl group at the -position of quinone group, exhibited the most potent inhibitory effects on HCT116, PC9, and A549 cells, with IC values decreasing from 5.27 to 1.18 μM (4.5-fold increase), 6.98 to 0.57 μM (12-fold increase), and 5.88 to 2.25 μM (2.6-fold increase), respectively, compared to compound . Further mechanistic studies revealed that compound significantly induced cell apoptosis by increasing the expression levels of cleaved caspase-3 and reducing Bcl-2 proteins through downregulating the EGFR/PI3K/Akt signalling pathway, leading to the inhibition of proliferation in HCT116 and PC9 cells. The present findings suggest this novel naphthoquinone-naphthol derivative may hold potential as an anticancer therapeutic lead.

In an attempt to create models of phosphodiesterases, we previously investigated bis(guanidinium) naphthols. Such metal‐free anion receptors cleaved aryl phosphates and also plasmid DNA. Observed reaction rates, however, could not compete with those of highly reactive metal complexes. In the present study, we have replaced the guanidines by ethylene diamine side chains which accelerates the plasmid cleavage by compound 13 significantly (1 mM 13: t1/2=22 h). Further gains in reactivity are achieved by azo coupling of the naphthol unit. The electron accepting azo group decreases the pKa of the hydroxy group. It can also serve as a dye label and a handle for attaching DNA binding moieties. The resulting azo naphthol 17 not only nicks (1 mM 17: t1/2~1 h) but also linearizes pUC19 DNA. Although the high reactivity of 17 seems to result in part from aggregation, in the presence of EDTA azo naphthol 17 obeys first order kinetics (1 mM 17: t1/2=4.8 h), reacts four times faster than naphthol 13 and surpasses by far the former bis(guanidinium) naphthols 4 and 5. Anion receptor 4 was shown previously to cleave phosphodiesters by nucleophilic substitution. It also nicks plasmid DNA to some extent. We have now replaced the guanidines by ethylene diamine side chains. By this modification, the resulting tetraamine 13 becomes an effective DNA cleaver (R=H). Azo coupling of 13 further boosts the reactivity of the resulting naphthols 16 and 17 (16: R=4‐carboxyphenylazo; 17: R=4‐methoxyphenylazo).

When faced with unfamiliar reaction space, synthetic chemists typically apply the reported conditions (reagents, catalyst, solvent and additives) of a successful reaction to a desired, closely related reaction using a new substrate type. Unfortunately, this approach often fails owing to subtle differences in reaction requirements. Consequently, an important goal in synthetic chemistry is the ability to transfer chemical observations quantitatively from one reaction to another. Here we present a holistic, data-driven workflow for deriving statistical models of one set of reactions that can be used to predict out-of-sample reactions. As a validating case study, we combined published enantioselectivity datasets that employ 1,1′-bi-2-naphthol (BINOL)-derived chiral phosphoric acids for a range of nucleophilic addition reactions to imines and developed statistical models. These models reveal the general interactions that impart asymmetric induction and allow the quantitative transfer of this information to new reaction components. This technique creates opportunities for translating comprehensive reaction analysis to diverse chemical space, streamlining both catalyst and reaction development. A workflow for deriving statistical models of one set of reactions that can be used to predict related reactions is presented, facilitating catalyst and enantioselective reaction development.

Chiral Brønsted acid-catalysed asymmetric synthesis has received tremendous interest over the past decades, and numerous efficient synthetic methods have been developed based on this approach. However, the use of chiral Brønsted acids in these reactions is mostly limited to the activation of imine and carbonyl moieties, and the direct activation of carbon–carbon triple bonds has so far not been invoked. Here we show that chiral Brønsted acids enable the catalytic asymmetric dearomatization reactions of naphthol-, phenol- and pyrrole-ynamides by the direct activation of alkynes. This method leads to the practical and atom-economic construction of various valuable spirocyclic enones and 2H-pyrroles that bear a chiral quaternary carbon stereocentre in generally good-to-excellent yields with excellent chemo-, regio- and enantioselectivities. The activation mode of chiral Brønsted acid catalysis revealed in this study is expected to be of broad utility in catalytic asymmetric reactions that involve ynamides and the related heteroatom-substituted alkynes.Chiral Brønsted acid catalysis is mostly limited to the activation of imine and carbonyl moieties. Now, by direct activation of alkynes, chiral Brønsted acids have been used to enable the catalytic asymmetric dearomatization of naphthol-, phenol- and pyrrole-ynamides for the construction of various spirocyclic enones and 2H-pyrroles bearing a chiral quaternary carbon stereocentre.

Cyanobacteria are ubiquitous organisms with a relevant contribution to primary production in all range of habitats. Cyanobacteria are well known for their part in worldwide occurrence of aquatic blooms while producing a myriad of natural compounds, some with toxic potential, but others of high economical impact, as geosmin. We performed an environmental survey of cyanobacterial soil colonies to identify interesting metabolic pathways and adaptation strategies used by these microorganisms and isolated, sequenced and assembled the genome of a cyanobacterium that displayed a distinctive earthy/musty smell, typical of geosmin, confirmed by GC-MS analysis of the culture’s volatile extract. Morphological studies pointed to a new Oscillatoriales soil ecotype confirmed by phylogenetic analysis, which we named Microcoleus asticus sp. nov. Our studies of geosmin gene presence in Bacteria, revealed a scattered distribution among Cyanobacteria, Actinobacteria, Delta and Gammaproteobacteria, covering different niches. Careful analysis of the bacterial geosmin gene and gene tree suggests an ancient bacterial origin of the gene, that was probably successively lost in different time frames. The high sequence similarities in the cyanobacterial geosmin gene amidst freshwater and soil strains, reinforce the idea of an evolutionary history of geosmin, that is intimately connected to niche adaptation.

The rise of multidrug-resistant (MDR) pathogens highlights the need for novel antimicrobial agents. This study reports the synthesis of two 1-aminoalkyl-2-naphthol derivatives, 1-(dimethylaminomethyl)naphthalen-2-ol ( 2 ) and 1-(piperidin-1-ylmethyl)naphthalen-2-ol ( 3 ), via the Betti base reaction using 2-naphthol, formaldehyde, and secondary amines. Structural confirmation was achieved through the 1 H and 13 C-NMR. Antimicrobial screening against 26 bacterial and 4 fungal strains revealed that compound 3 exhibited potent antibacterial activity against MDR strains, with a minimum inhibitory concentration (MIC) value as low as 10 µg/mL against Pseudomonas aeruginosa MDR1. Compound 3 also demonstrated superior efficacy against Staphylococcus aureus MDR strains, with an MIC of 100 µg/mL, compared to ciprofloxacin, which had an MIC of 200 µg/mL. Its lower MIC values compared to ciprofloxacin suggests that compound 3 has potential for treating infections caused by multidrug-resistant S. aureus . Compound 2 showed strong antifungal activity against Penicillium notatum and P. funiculosum , with an MIC of 400 µg/mL, outperforming griseofulvin (MIC = 500 µg/mL). Molecular docking further supported these findings, with compound 3 displaying strong binding affinities to E. coli DNA gyrase (‒6.755 kcal/mol; PDB ID: 5MMN) and Candida albicans lanosterol 14α-demethylase (‒7.813 kcal/mol; PDB ID: 5V5Z). Overall, these results underscore the potential of 1-aminoalkyl-2-naphthol derivatives as promising candidates for combating drug-resistant infections.

Axially chiral biaryls, as exemplified by 1,1′-bi-2-naphthol (BINOL), are key components of catalysts, natural products and medicines. These materials are synthesized conventionally in enantioenriched form through metal-mediated cross coupling, de novo construction of an aromatic ring, point-to-axial chirality transfer or an atropselective transformation of an existing biaryl. Here, we report a highly enantioselective organocatalytic method for the synthesis of atropisomeric biaryls by a cation-directed O -alkylation. Treatment of racemic 1-aryl-2-tetralones with a chiral quinidine-derived ammonium salt under basic conditions in the presence of an alkylating agent leads to atropselective O -alkylation with e.r. up to 98:2. Oxidation with DDQ gives access to C 2 -symmetric and non-symmetric BINOL derivatives without compromising e.r. We propose that the chiral ammonium counterion differentiates between rapidly equilibrating atropisomeric enolates, leading to highly atropselective O -alkylation. This dynamic kinetic resolution process offers a general approach to the synthesis of enantioenriched atropisomeric materials. A chiral ammonium salt mediates a dynamic kinetic resolution of racemic α-aryl ketones by atropselective O -alkylation. Oxidation with DDQ gives access to C 2 -symmetric and non-symmetric BINOL derivatives in high yields and with high enantioselectivity.