Shapeshifting bullvalene-linked vancomycin dimers as effective antibiotics against multidrug-resistant gram-positive bacteria.

The alarming rise in superbugs that are resistant to drugs of last resort, including vancomycin-resistant enterococci and staphylococci, has become a significant global health hazard. Here, we report the click chemistry synthesis of an unprecedented class of shapeshifting vancomycin dimers (SVDs) that display potent activity against bacteria that are resistant to the parent drug, including the ESKAPE pathogens, vancomycin-resistant Enterococcus (VRE), methicillin-resistant Staphylococcus aureus (MRSA), as well as vancomycin-resistant S. aureus (VRSA). The shapeshifting modality of the dimers is powered by a triazole-linked bullvalene core, exploiting the dynamic covalent rearrangements of the fluxional carbon cage and creating ligands with the capacity to inhibit bacterial cell wall biosynthesis. The new shapeshifting antibiotics are not disadvantaged by the common mechanism of vancomycin resistance resulting from the alteration of the C-terminal dipeptide with the corresponding d-Ala-d-Lac depsipeptide. Further, evidence suggests that the shapeshifting ligands destabilize the complex formed between the flippase MurJ and lipid II, implying the potential for a new mode of action for polyvalent glycopeptides. The SVDs show little propensity for acquired resistance by enterococci, suggesting that this new class of shapeshifting antibiotic will display durable antimicrobial activity not prone to rapidly acquired clinical resistance.

Diversity oriented clicking delivers ß-substituted alkenyl sulfonyl fluorides as covalent human neutrophil elastase inhibitors.

Diversity Oriented Clicking (DOC) is a discovery method geared toward the rapid synthesis of functional libraries. It combines the best attributes of both classical and modern click chemistries. DOC strategies center upon the chemical diversification of core "SuFExable" hubs-exemplified by 2-Substituted-Alkynyl-1-Sulfonyl Fluorides (SASFs)-enabling the modular assembly of compounds through multiple reaction pathways. We report here a range of stereoselective Michael-type addition pathways from SASF hubs including reactions with secondary amines, carboxylates, 1H-1,2,3-triazole, and halides. These high yielding conjugate addition pathways deliver unprecedented ß-substituted alkenyl sulfonyl fluorides as single isomers with minimal purification, greatly enriching the repertoire of DOC and holding true to the fundamentals of modular click chemistry. Further, we demonstrate the potential for biological function - a key objective of click chemistry - of this family of SASF-derived molecules as covalent inhibitors of human neutrophil elastase.

Firearm Safety Counseling in Pediatric Primary Care.

Injury from firearms is the leading cause of death among children and adolescents in the United States. Prevention requires a multi-pronged approach involving clinicians and policy. One evidence-based method to improve firearm safety is counseling with lock provision. Through sharing our experiences, we aim to inspire more health care practices to adopt firearm safety prevention strategies.

Ethene-1,1-disulfonyl Difluoride (EDSF) for SuFEx Click Chemistry: Synthesis of SuFExable 1,1-Bissulfonylfluoride Substituted Cyclobutene Hubs.

We present the synthesis of 1,1-bis(fluorosulfonyl)-2-(pyridin-1-ium-1-yl)ethan-1-ide, a bench-stable precursor to ethene-1,1-disulfonyl difluoride (EDSF). The novel SuFEx reagent, EDSF, is demonstrated in the preparation of 26 unique 1,1-bissulfonylfluoride substituted cyclobutenes via a cycloaddition reaction. The regioselective click cycloaddition reaction is rapid, straightforward, and highly efficient, enabling the generation of highly functionalized 4-membered ring (4MR) carbocycles. These carbocycles are valuable structural motifs found in numerous bioactive natural products and pharmaceutically relevant small molecules. Additionally, we showcase diversification of the novel cyclobutene cores through selective Cs2 CO3 -activated SuFEx click chemistry between a single S-F group and an aryl alcohol, yielding the corresponding sulfonate ester products with high efficiency. Finally, density functional theory calculations offer mechanistic insights about the reaction pathway.

SuFEx-enabled, agnostic discovery of covalent inhibitors of human neutrophil elastase.

Sulfur fluoride exchange (SuFEx) has emerged as the new generation of click chemistry. We report here a SuFEx-enabled, agnostic approach for the discovery and optimization of covalent inhibitors of human neutrophil elastase (hNE). Evaluation of our ever-growing collection of SuFExable compounds toward various biological assays unexpectedly revealed a selective and covalent hNE inhibitor: benzene-1,2-disulfonyl fluoride. Synthetic derivatization of the initial hit led to a more potent agent, 2-(fluorosulfonyl)phenyl fluorosulfate with IC50 0.24 µM and greater than 833-fold selectivity over the homologous neutrophil serine protease, cathepsin G. The optimized, yet simple benzenoid probe only modified active hNE and not its denatured form.

No evidence of lymphatic filariasis transmission in Bamako urban setting after three mass drug administration rounds.

Lymphatic filariasis (LF) elimination activities started in Mali in 2005 in the most endemic areas and reached countrywide coverage in 2009. In 2004, the district of Bamako was endemic for LF with a prevalence of 1.5%. The current study was designed to determine LF endemicity level in the urban area of Bamako after three rounds of ivermectin and albendazole mass drug administration (MDA). A cross-sectional study was conducted in 2011 in Bamako city, consisting of human prevalence and entomological surveys. Volunteers aged 14 years and above were invited to participate and tested for evidence of Wuchereria bancrofti using night time blood thick smear microfilarial count and blood spots for LF antibodies using the SD BIOLINE Oncho/LF IgG4 Biplex rapid test (Ov16/Wb123). Mosquitoes were collected using CDC light and gravid traps and tested using molecular methods. Poolscreen software v2.0 was used to estimate vector transmission potential. Of the 899 volunteers, one (0.11%) was found to be positive for LF using the Oncho/LF IgG4 Biplex rapid test, and none was found to have Wuchereria bancrofti microfilariae. No mosquitoes were found infected among 6174 Culex spp. (85.2%), 16 Anopheles gambiae s.l. (An. gambiae s.l.) (0.2%), 26 Aedes spp. (0.4%), 858 Ceratopogonidae (11.8%) and 170 other insects not identified (2.3%) tested. Our data indicate that there was no active LF transmission in the low prevalence urban district of Bamako after three MDA rounds. These data helped the National LF programme move forward towards the elimination goal.

Accelerated SuFEx Click Chemistry For Modular Synthesis.

SuFEx click chemistry is a powerful method designed for the selective, rapid, and modular synthesis of functional molecules. Classical SuFEx reactions form stable S-O linkages upon exchange of S-F bonds with aryl silyl-ether substrates, and while near-perfect in their outcome, are sometimes disadvantaged by relatively high catalyst loadings and prolonged reaction times. We herein report the development of accelerated SuFEx click chemistry (ASCC), an improved SuFEx method for the efficient and catalytic coupling of aryl and alkyl alcohols with a range of SuFExable hubs. We demonstrate Barton's hindered guanidine base (2-tert-butyl-1,1,3,3-tetramethylguanidine; BTMG) as a superb SuFEx catalyst that, when used in synergy with silicon additive hexamethyldisilazane (HMDS), yields stable S-O bond linkages in a single step; often within minutes. The powerful combination of BTMG and HMDS reagents allows for catalyst loadings as low as 1.0 mol % and, in congruence with click-principles, provides a scalable method that is safe, efficient, and practical for modular synthesis. ASSC expands the number of accessible SuFEx products and will find significant application in organic synthesis, medicinal chemistry, chemical biology, and materials science.

Mechanism of intersubunit ketosynthase-dehydratase interaction in polyketide synthases.

Modular polyketide synthases (PKSs) produce numerous structurally complex natural products that have diverse applications in medicine and agriculture. PKSs typically consist of several multienzyme subunits that utilize structurally defined docking domains (DDs) at their N and C termini to ensure correct assembly into functional multiprotein complexes. Here we report a fundamentally different mechanism for subunit assembly in trans-acyltransferase (trans-AT) modular PKSs at the junction between ketosynthase (KS) and dehydratase (DH) domains. This mechanism involves direct interaction of a largely unstructured docking domain (DD) at the C terminus of the KS with the surface of the downstream DH. Acyl transfer assays and mechanism-based crosslinking established that the DD is required for the KS to communicate with the acyl carrier protein appended to the DH. Two distinct regions for binding of the DD to the DH were identified using NMR spectroscopy, carbene footprinting, and mutagenesis, providing a foundation for future elucidation of the molecular basis for interaction specificity.

Diversity Oriented Clicking (DOC): Divergent Synthesis of SuFExable Pharmacophores from 2-Substituted-Alkynyl-1-Sulfonyl Fluoride (SASF) Hubs.

Diversity Oriented Clicking (DOC) is a unified click-approach for the modular synthesis of lead-like structures through application of the wide family of click transformations. DOC evolved from the concept of achieving "diversity with ease", by combining classic C-C π-bond click chemistry with recent developments in connective SuFEx-technologies. We showcase 2-Substituted-Alkynyl-1-Sulfonyl Fluorides (SASFs) as a new class of connective hub in concert with a diverse selection of click-cycloaddition processes. Through the selective DOC of SASFs with a range of dipoles and cyclic dienes, we report a diverse click-library of 173 unique functional molecules in minimal synthetic steps. The SuFExable library comprises 10 discrete heterocyclic core structures derived from 1,3- and 1,5-dipoles; while reaction with cyclic dienes yields several three-dimensional bicyclic Diels-Alder adducts. Growing the library to 278 discrete compounds through late-stage modification was made possible through SuFEx click derivatization of the pendant sulfonyl fluoride group in 96 well-plates-demonstrating the versatility of the DOC approach for the rapid synthesis of diverse functional structures. Screening for function against MRSA (USA300) revealed several lead hits with improved activity over methicillin.

Metal-Free Synthesis of Functional 1-Substituted-1,2,3-Triazoles from Ethenesulfonyl Fluoride and Organic Azides.

The boom in growth of 1,4-disubstituted triazole products, in particular, since the early 2000's, can be largely attributed to the birth of click chemistry and the discovery of the CuI -catalyzed azide-alkyne cycloaddition (CuAAC). Yet the synthesis of relatively simple, albeit important, 1-substituted-1,2,3-triazoles has been surprisingly more challenging. Reported here is a straightforward and scalable click-inspired protocol for the synthesis of 1-substituted-1,2,3-triazoles from organic azides and the bench stable acetylene surrogate ethenesulfonyl fluoride (ESF). The new transformation tolerates a wide selection of substrates and proceeds smoothly under metal-free conditions to give the products in excellent yield. Under controlled acidic conditions, the 1-substituted-1,2,3-triazole products undergo a Michael addition reaction with a second equivalent of ESF to give the unprecedented 1-substituted triazolium sulfonyl fluoride salts.

Community awareness of diet needs associated with hypertension and type 2 diabetes mellitus in Hatcliffe, Zimbabwe.

BACKGROUND: Diet is an important modifiable risk factor for non-communicable diseases (NCDs) like hypertension (HTN) and type 2 diabetes mellitus (T2DM). A NCD is a disease that cannot be transmitted from person to person. Dietary risk factors account for 5.8% of all-cause mortality in Sub-Saharan Africa (SSA). There has been an increase in the consumption of 'westernized 'diets in SSA. The westernized diets consumed in low-income countries are usually high in salt content, fatty, processed and fast foods; and hence accelerate the development of HTN and T2DM. Previous studies carried out in Zimbabwe showed low levels of knowledge and awareness of HTN and T2DM; and the dietary needs for patients with those conditions. The aim of this study was to explore the dietary habits and awareness of HTN and T2DM of both males and females in a high-density area (HDA) of Zimbabwe. METHODS: We conducted household-based cross-sectional study in a high density area of Hatcliffe, which has a population of close to 50,000 residents. Face to face interviews were conducted using hand-held mobile devices loaded with KoBo Toolbox. We selected two consenting adults, a male and female, from every fourth household in selected areas of Hatcliffe. RESULTS: In this study all the 492 participants that were interviewed responded. Eighty eight point 6% (88.6%) of the participants in the study did not know if they were hypertensive or not. In addition, 91.7% of the participants had never voluntarily checked for hypertension. Similarly, 97.6% of the participants did not know if they had T2DM or not. Ninety eight percent (98%) of the participants had not voluntarily checked their blood glucose level. CONCLUSIONS: The majority of the participants in the study were not aware if they had HTN or T2DM. The participants in the study perceived that the salt they consume is the right quantity. There is a high consumption of vegetable oil in most meals prepared.

A prospective risk assessment of the implementation of a schistosomiasis preventive mass drug administration for children aged five years and below in the uMkhanyakude district of KwaZulu-Natal.

BACKGROUND: Schistosomiasis is endemic in the uMkhanyakude district of KwaZulu-Natal, South Africa. The South Africa Department of Health (DoH) has decided to implement a schistosomiasis preventive mass drug administration program in all affected parts of the country. Quality management is part of the strategic objectives of the treatment program. We conducted a risk assessment and developed guidelines for the quality management of a schistosomiasis preventive treatment program for children aged 5 years and below in the uMkhanyakude District of KwaZulu-Natal. METHODS: We conducted a scenario planning exercise by interviewing 10 child health experts from the uMkhanyakude Health District to establish potential risks associated with a planned schistosomiasis preventive control treatment program for children aged 5 years old and below. The risks were analyzed using a modified Failure Mode and Effect Analysis (FMEA). An FMEA table was produced to guide the quality management of the planned schistosomiasis preventive control treatment program for children aged 5 years and below in the uMkhanyakude Health District. RESULTS: We identified potential risks, failure modes and possible failure corrective/preventive measures in the following activities that would be part of the mass treatment of children aged 5 years and below infected with schistosomiasis in the uMkhanyakude District. These included enrolment of children into the treatment program; general health checks; weight and height measurements; administration of drugs; reporting of side effects and monitoring and evaluation. CONCLUSION: We were able to use FMEA guide quality management and identify potential risks associated with the planned schistosomiasis preventive treatment program for children aged 5 years old and below in the uMkhanyakude District of KwaZulu-Natal. The FMEA for this program will be useful to the quality management of schistosomiasis preventive treatment programs for this age group in other similar settings.

Biocompatible SuFEx Click Chemistry: Thionyl Tetrafluoride (SOF4 )-Derived Connective Hubs for Bioconjugation to DNA and Proteins.

We report here the development of a suite of biocompatible SuFEx transformations from the SOF4 -derived iminosulfur oxydifluoride hub in aqueous buffer conditions. These biocompatible SuFEx reactions of iminosulfur oxydifluorides (R-N=SOF2 ) with primary amines give sulfamides (8 examples, up to 98 %), while the reaction with secondary amines furnish sulfuramidimidoyl fluoride products (8 examples, up to 97 %). Likewise, under mild buffered conditions, phenols react with the iminosulfur oxydifluorides (Ar-N=SOF2 ) to produce sulfurofluoridoimidates (13 examples, up to 99 %), which can themselves be further modified by nucleophiles. These transformations open the potential for asymmetric and trisubstituted linkages projecting from the sulfur(VI) center, including versatile S-N and S-O connectivity (9 examples, up to 94 %). Finally, the SuFEx bioconjugation of iminosulfur oxydifluorides to amine-tagged single-stranded DNA and to BSA protein demonstrate the potential of SOF4 -derived SuFEx click chemistry in biological applications.

Bifluoride Ion Mediated SuFEx Trifluoromethylation of Sulfonyl Fluorides and Iminosulfur Oxydifluorides.

SuFEx is a new-generation click chemistry transformation that exploits the unique properties of S-F bonds and their ability to undergo near-perfect reactions with nucleophiles. We report here the first SuFEx-based procedure for the efficient synthesis of pharmaceutically important triflones and bis(trifluoromethyl)sulfur oxyimines from sulfonyl fluorides and iminosulfur oxydifluorides, respectively. The new process involves rapid S-F exchange with trifluoromethyltrimethylsilane (TMSCF3 ) upon activation by potassium bifluoride in anhydrous DMSO. The reaction tolerates a wide selection of substrates and proceeds under mild conditions without need for chromatographic purification. A tentative mechanism is proposed involving nucleophilic displacement of S-F by the trifluoromethyl anion via a five-coordinate intermediate. The utility of late-stage SuFEx trifluoromethylation is demonstrated through the synthesis and selective anticancer properties of a bis(trifluoromethyl)sulfur oxyimine.

Quantitative and Orthogonal Formation and Reactivity of SuFEx Platforms.

The constraints of minute reactant amounts and the impossibility to remove any undesired surface-bound products during monolayer functionalization of a surface necessitate the selection of efficient, modular and orthogonal reactions that lead to quantitative conversions. Herein, we explore the character of sulfur-fluoride exchange (SuFEx) reactions on a surface, and explore the applicability for quantitative and orthogonal surface functionalization. To this end, we demonstrate the use of ethenesulfonyl fluoride (ESF) as an efficient SuFEx linker for creating "SuFEx-able" monolayer surfaces, enabling three distinct approaches to utilize SuFEx chemistry on a surface. The first approach relies on a di-SuFEx loading allowing dual functionalization with a nucleophile, while the two latter approaches focus on dual (CuAAC-SuFEx/SPOCQ-SuFEx) click platforms. The resultant strategies allow facile attachment of two different substrates sequentially on the same platform. Along the way we also demonstrate the Michael addition of ethenesulfonyl fluoride to be a quantitative surface-bound reaction, indicating significant promise in materials science for this reaction.

Modification of Carbon Fibre Surfaces by Sulfur-Fluoride Exchange Click Chemistry.

Technologies that enable surface modification are in high demand and are critical for the implementation of new functional materials and devices. Here, we describe the first modification of a carbon surface (in this case carbon fiber) using the sulfur-fluoride exchange (SuFEx) reaction. The parent sulfur (VI) fluoride moiety can be installed directly to the surface via electrochemical deposition of the fluorosulfate phenyldiazonium tetrafluoroborate salt, or by 'SuFExing' a phenol on the carbon surface followed by treatment of the material with SO2 F2 ; similar to a 'graft to' or 'graft from' functionalization approach. We demonstrate that these SuFEx-able surfaces readily undergo exchange with aryl silyl ethers, and that the subsequent sulfate linkages are themselves stable under electrochemical redox conditions. Finally, we showcase the utility of the SuFEx chemistry by installing a pendant amino group to the fiber surface resulting in interfacial shear strength improvements of up to 130 % in epoxy resin.

SuFEx Chemistry of Thionyl Tetrafluoride (SOF4 ) with Organolithium Nucleophiles: Synthesis of Sulfonimidoyl Fluorides, Sulfoximines, Sulfonimidamides, and Sulfonimidates.

Thionyl tetrafluoride (SOF4 ) is a valuable connective gas for sulfur fluoride exchange (SuFEx) click chemistry that enables multidimensional linkages to be created via sulfur-oxygen and sulfur-nitrogen bonds. Herein, we expand the available SuFEx chemistry of SOF4 to include organolithium nucleophiles, and demonstrate, for the first time, the controlled projection of sulfur-carbon links at the sulfur center of SOF4 -derived iminosulfur oxydifluorides (R1 -N=SOF2 ). This method provides rapid and modular access to sulfonimidoyl fluorides (R1 -N=SOFR2 ), another array of versatile SuFEx connectors with readily tunable reactivity of the S-F handle. Divergent connections derived from these valuable sulfonimidoyl fluoride units are also demonstrated, including the synthesis of sulfoximines, sulfonimidamides, and sulfonimidates.

Reengineering Antibiotics to Combat Bacterial Resistance: Click Chemistry [1,2,3]-Triazole Vancomycin Dimers with Potent Activity against MRSA and VRE.

Vancomycin has long been considered a drug of last resort. Its efficiency in treating multiple drug-resistant bacterial infections, particularly methicillin-resistant Staphylococcus aureus (MRSA), has had a profound effect on the treatment of life-threatening infections. However, the emergence of resistance to vancomycin is a cause for significant worldwide concern, prompting the urgent development of new effective treatments for antibiotic resistant bacterial infections. Harnessing the benefits of multivalency and cooperativity against vancomycin-resistant strains, we report a Click Chemistry approach towards reengineered vancomycin derivatives and the synthesis of a number of dimers with increased potency against MRSA and vancomycin resistant Enterococci (VRE; VanB). These semi-synthetic dimeric ligands were linked together with great efficiency using the powerful CuAAC reaction, demonstrating high levels of selectivity and purity.

Sulfur-Fluoride Exchange (SuFEx)-Mediated Synthesis of Sterically Hindered and Electron-Deficient Secondary and Tertiary Amides via Acyl Fluoride Intermediates.

Amide bond formation is one of the most executed reactions in chemistry and biology. This is largely due to the ubiquity of the amide functional group in biological molecules, natural products and pharmaceutically important drugs. We report here the development of "SuFExAmide": a new sulfur-fluoride exchange (SuFEx) click chemistry based protocol for the efficient amidation of carboxylic acids via acyl fluoride intermediates. We have developed benzene-1,3-disulfonyl fluoride as a cost effective, powerful and versatile coupling agent, which delivers challenging secondary and tertiary amides in excellent yields from sterically hindered and electron-deficient amines. The straightforward method offers significant benefits over existing protocols in terms of substrate scope, efficiency and ease of operation and is demonstrated by the synthesis of 44 amides, including GNF6702, an antiprotozoal drug candidate. In the majority of cases, the amide products are obtained in high yield without the need for excess reagents or chromatographic purification.