Synthesis of Cyclopropanes via Hydrogen-Borrowing Catalysis.

Cyclopropanes are highly useful motifs that are often incorporated into drug candidates to improve potency, metabolic stability, or pharmacokinetic properties. An expedient method for the α-cyclopropanation of ketones using hydrogen borrowing (HB) catalysis is described. The transformation occurs via HB alkylation of a hindered ketone with subsequent intramolecular displacement of a pendant leaving group affording the cyclopropanated product. The leaving group can be installed in either the ketone or alcohol component of the HB system, giving access to α-cyclopropyl ketones via two complementary approaches. Conversion to the corresponding carboxylic acids can be achieved in a simple two-step sequence to afford synthetically useful 1,1-substituted spirocyclopropyl acid building blocks.

Evaluation of three immunological assays to mitigate the risk of transboundary spread of Coxiella burnetii by alpacas.

Coxiella burnetii causes coxiellosis in animals and Q fever in humans, a potentially debilitating zoonotic disease commonly transmitted through domestic ruminants. To prevent transboundary spread of C. burnetii, animals may be tested prior to export. In alpacas, this process is complicated by the lack of scientific evidence for C. burnetii infection in the species, and the unique composition of camelid antibodies, which may cause false-positive results in assays developed for ruminants. We evaluated a complement fixation test (CFT; currently recommended for alpacas in New Zealand), an enzyme-linked immunosorbent assay (ELISA) and an immunofluorescence assay (IFA). Positive analytical control samples were generated through vaccination of alpacas with a human Q fever vaccine, whereas negative analytical control samples were sourced from New Zealand (deemed free of C. burnetii). Immunological assays were conducted on 131 alpaca sera submitted for export testing. Test characteristics (sensitivity, specificity, positive and negative predictive values) for CFT, ELISA and IFA were determined using Bayesian latent class analysis. Due to anticomplementary activity, 37 (28.2%) of the CFT results were inconclusive, making CFT unsuitable for routine use. Of the remaining 94 samples, 10.6%, 0% and 7.4% were positive for C. burnetii antibodies based on CFT, ELISA and IFA, respectively, yielding estimated sensitivities of 58%, 26% and 78%, and estimated specificities of 95%, 98% and 95%, with the estimates for sensitivity being imprecise, as evidenced by wide 95% credible intervals. Positive predictive values were similar across assays, albeit very low at the estimated seroprevalence of 5%. Our results indicate that, of the tests available, IFA appears to be the most appropriate for use in alpacas. Higher sensitivity of antibody detection, use of antigen detection assays and availability of samples from individuals with evidence of infection could provide additional insight into the risk of transboundary spread of C. burnetii by alpacas.

Correction: The multifaceted nature of antimicrobial peptides: current synthetic chemistry approaches and future directions.

Correction for 'The multifaceted nature of antimicrobial peptides: current synthetic chemistry approaches and future directions' by Bee Ha Gan et al., Chem. Soc. Rev., 2021, 50, 7820-7880, DOI: 10.1039/D0CS00729C.

Energetics of lipid transport by the ABC transporter MsbA is lipid dependent.

The ABC multidrug exporter MsbA mediates the translocation of lipopolysaccharides and phospholipids across the plasma membrane in Gram-negative bacteria. Although MsbA is structurally well characterised, the energetic requirements of lipid transport remain unknown. Here, we report that, similar to the transport of small-molecule antibiotics and cytotoxic agents, the flopping of physiologically relevant long-acyl-chain 1,2-dioleoyl (C18)-phosphatidylethanolamine in proteoliposomes requires the simultaneous input of ATP binding and hydrolysis and the chemical proton gradient as sources of metabolic energy. In contrast, the flopping of the large hexa-acylated (C12-C14) Lipid-A anchor of lipopolysaccharides is only ATP dependent. This study demonstrates that the energetics of lipid transport by MsbA is lipid dependent. As our mutational analyses indicate lipid and drug transport via the central binding chamber in MsbA, the lipid availability in the membrane can affect the drug transport activity and vice versa.

The multifaceted nature of antimicrobial peptides: current synthetic chemistry approaches and future directions.

Bacterial infections caused by 'superbugs' are increasing globally, and conventional antibiotics are becoming less effective against these bacteria, such that we risk entering a post-antibiotic era. In recent years, antimicrobial peptides (AMPs) have gained significant attention for their clinical potential as a new class of antibiotics to combat antimicrobial resistance. In this review, we discuss several facets of AMPs including their diversity, physicochemical properties, mechanisms of action, and effects of environmental factors on these features. This review outlines various chemical synthetic strategies that have been applied to develop novel AMPs, including chemical modifications of existing peptides, semi-synthesis, and computer-aided design. We will also highlight novel AMP structures, including hybrids, antimicrobial dendrimers and polypeptides, peptidomimetics, and AMP-drug conjugates and consider recent developments in their chemical synthesis.

The role of chemical synthesis in developing RiPP antibiotics.

The growing antimicrobial resistance crisis necessitates the discovery and development of novel classes of antibiotics if a 'postantibiotic era' is to be avoided. Ribosomally synthesised and post-translationally modified peptides, or RiPPs, are becoming increasingly recognised as a potential source of antimicrobial drugs. This is due to a combination of their potent antimicrobial activity and their high stability relative to unmodified linear peptides. However, as peptide drugs, their clinical development is often perturbed by issues such as low solubility and poor bioavailability. Chemical synthesis has the potential to overcome some of these challenges. Furthermore, the structural complexity of RiPPs makes them interesting synthetic targets in their own right, with the total synthesis of some structural classes having only been recently realised. This review focusses on the use of RiPPs as antimicrobial agents and will highlight various strategies that have been employed to chemically synthesise three major classes of RiPPs: lasso peptides, cyclotides, and lanthipeptides.

Macrocyclisation and functionalisation of unprotected peptides via divinyltriazine cysteine stapling.

We report a novel divinyltriazine linker for the stapling of two cysteine residues to form macrocyclic peptides from their unprotected linear counterparts. The stapling reaction occurred rapidly under mild conditions on a range of unprotected peptide sequences. The resulting constrained peptides displayed greater stability in a serum stability assay when compared to their linear counterparts.

Asymmetric Syntheses of (+)-Preussin B, the C(2)-Epimer of (-)-Preussin B, and 3-Deoxy-(+)-preussin B.

Efficient de novo asymmetric syntheses of (+)-preussin B, the C(2)-epimer of (-)-preussin B, and 3-deoxy-(+)-preussin B have been developed, using the diastereoselective conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide to tert-butyl 4-phenylbut-2-enoate and diastereoselective reductive cyclizations of γ-amino ketones as the key steps to set the stereochemistry. Conjugate addition followed by enolate protonation generated the corresponding ß-amino ester. Homologation using the ester functionality as a synthetic handle gave the corresponding γ-amino ketone. Hydrogenolytic N-debenzylation was accompanied by diastereoselective reductive cyclization in situ; reductive N-methylation then gave 3-deoxy-(+)-preussin B as the major diastereoisomeric product. Meanwhile, the same conjugate addition but followed by enolate oxidation with (+)-camphorsulfonyloxaziridine gave the corresponding anti-α-hydroxy-ß-amino ester. α-Epimerization by oxidation and diastereoselective reduction then gave access to the corresponding syn-α-hydroxy-ß-amino ester. Homologation of both of these diastereoisomeric α-hydroxy-ß-amino esters gave the corresponding ß-hydroxy-γ-amino ketones. N-Debenzylation and concomitant diastereoselective reductive cyclization, followed by reductive N-methylation, provided the C(2)-epimer of (-)-preussin B and (+)-preussin B as the major diastereoisomeric products, respectively. The overall yields (from phenylacetaldehyde) were 19% for 3-deoxy-(+)-preussin B over seven steps, 8% for the C(2)-epimer of (-)-preussin B over nine steps, and 7% for (+)-preussin B over eleven steps.