Enhancing allosteric inhibition of dihydrodipicolinate synthase through the design and synthesis of novel dimeric compounds.

The synthesis of the first dimeric inhibitor of dihydrodipicolinate synthase (DHDPS) is reported herein. Inspired by 2,4-thiazolidinedione based ligands previously shown to inhibit DHDPS, a series of dimeric inhibitors were designed and synthesised, incorporating various alkyl chain bridges between two 2,4-thiazolidinedione moieties. Aiming to exploit the multimeric nature of this enzyme and enhance potency, a dimeric compound with a single methylene bridge achieved the desired outcome with low micromolar inhibition of DHDPS observed.

Repurposed inhibitor of bacterial dihydrodipicolinate reductase exhibits effective herbicidal activity.

Herbicide resistance represents one of the biggest threats to our natural environment and agricultural sector. Thus, new herbicides are urgently needed to tackle the rise in herbicide-resistant weeds. Here, we employed a novel strategy to repurpose a 'failed' antibiotic into a new and target-specific herbicidal compound.

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 (VRE), methicillin-resistant (MRSA), as well as vancomycin-resistant (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.

Cage hydrocarbons as linkers in dimeric drug design: Case studies with trimethoprim and tedizolid.

The looming threat of a "post-antibiotic era" has been caused by a rapid rise in antibacterial resistance and subsequent depletion of effective antibiotic agents in the clinic. An efficient strategy to address this shortfall lies in the reengineering of pre-existing and commercially available antibiotic drugs. This is exemplified by dimerization, a design concept in which two pharmacophores are covalently linked to form a new chemical entity.

Structural insight into the Scribble PDZ domains interaction with the oncogenic Human T-cell lymphotrophic virus-1 (HTLV-1) Tax1 PBM.

Scribble (Scrib) is a highly conserved cell polarity regulator that harbours potent tumour suppressor activity and plays an important role in cell migration. Dysregulation of polarity is associated with poor prognosis during viral infections. Human T-cell lymphotrophic virus-1 (HTLV-1) encodes for the oncogenic Tax1 protein, a modulator of the transcription of viral and human proteins that can cause cell cycle dysregulation as well as a loss of genomic integrity.

Structural characterisation of a MAPR-related archaeal cytochrome b protein.

We recently reported that the membrane-associated progesterone receptor (MAPR) protein family (mammalian members: PGRMC1, PGRMC2, NEUFC and NENF) originated from a new class of prokaryotic cytochrome b (cytb ) domain proteins, called cytb (MAPR-like). Relative to classical cytb proteins, MAPR and ctyb proteins shared unique sequence elements and a distinct heme-binding orientation at an approximately 90° rotation relative to classical cytb , as demonstrated in the archetypal crystal structure of a cytb protein (PDB accession number 6NZX). Here, we present the crystal structure of an archaeal cytb domain (Methanococcoides burtonii WP_011499504.

Biosynthesis of uridine diphosphate N-Acetylglucosamine: An underexploited pathway in the search for novel antibiotics?

Although the prevalence of antibiotic resistance is increasing at an alarming rate, there are a dwindling number of effective antibiotics available. Thus, the development of novel antibacterial agents should be of utmost importance. Peptidoglycan biosynthesis has been and is still an attractive source for antibiotic targets; however, there are several components that remain underexploited.

Antibacterial silver and gold complexes of imidazole and 1,2,4-triazole derived N-heterocyclic carbenes.

A series of gold(I) (4a-4h, 5a-5b) and silver(I) (3a-3h) complexes of 1,2,4-triazolylidene and imidazolylidene based N-heterocyclic carbene ligands were prepared and the antibacterial activities of these complexes have been evaluated. The complexes were characterised using H-NMR, C-NMR, HRMS and in the cases of 3a, 3c, 4b and 5b by X-ray crystallography. The gold(I) complexes with phenyl substituents (4a-4d) were found to have potent antibacterial activity against Gram-positive bacteria, with the complexes of the 1,2,4-triazolylidene ligands being more active (4c, MIC = 4-8 μg mL against and 2 μg mL against ) than the analogous imidazolylidene complexes 4a and 4b (4a, MIC = 64 μg mL against and 2-4 μg mL against ).

A dual-target herbicidal inhibitor of lysine biosynthesis.

Herbicides with novel modes of action are urgently needed to safeguard global agricultural industries against the damaging effects of herbicide-resistant weeds. We recently developed the first herbicidal inhibitors of lysine biosynthesis, which provided proof-of-concept for a promising novel herbicide target. In this study, we expanded upon our understanding of the mode of action of herbicidal lysine biosynthesis inhibitors.

Synthesis and structure-activity relationship studies of 2,4-thiazolidinediones and analogous heterocycles as inhibitors of dihydrodipicolinate synthase.

Dihydrodipicolinate synthase (DHDPS), responsible for the first committed step of the diaminopimelate pathway for lysine biosynthesis, has become an attractive target for the development of new antibacterial and herbicidal agents. Herein, we report the discovery and exploration of the first inhibitors of E. coli DHDPS which have been identified from screening lead and are not based on substrates from the lysine biosynthesis pathway.

Fc Binding by FcγRIIa Is Essential for Cellular Activation by the Anti-FcγRIIa mAbs 8.26 and 8.2.

FcγR activity underpins the role of antibodies in both protective immunity and auto-immunity and importantly, the therapeutic activity of many monoclonal antibody therapies. Some monoclonal anti-FcγR antibodies activate their receptors, but the properties required for cell activation are not well defined. Here we examined activation of the most widely expressed human FcγR; FcγRIIa, by two non-blocking, mAbs, 8.

Structural and biochemical analyses of concanavalin A circular permutation by jack bean asparaginyl endopeptidase.

Over 30 years ago, an intriguing posttranslational modification was found responsible for creating concanavalin A (conA), a carbohydrate-binding protein from jack bean (Canavalia ensiformis) seeds and a common carbohydrate chromatography reagent. ConA biosynthesis involves what was then an unprecedented rearrangement in amino-acid sequence, whereby the N-terminal half of the gene-encoded conA precursor (pro-conA) is swapped to become the C-terminal half of conA. Asparaginyl endopeptidase (AEP) was shown to be involved, but its mechanism was not fully elucidated.

Overcoming Intrinsic and Acquired Resistance Mechanisms Associated with the Cell Wall of Gram-Negative Bacteria.

The global increase in multi-drug-resistant bacteria is severely impacting our ability to effectively treat common infections. For Gram-negative bacteria, their intrinsic and acquired resistance mechanisms are heightened by their unique cell wall structure. The cell wall, while being a target of some antibiotics, represents a barrier due to the inability of most antibacterial compounds to traverse and reach their intended target.

Synthesis, conformational analysis and antibacterial activity of Au(I)-Ag(I) and Au(I)-Hg(II) heterobimetallic N-heterocyclic carbene complexes.

A post-synthetic modification and metallation procedure has been used to prepare a family of heterobimetallic Au(i)-Ag(i) and Au(i)-Hg(ii) complexes featuring either symmetrical or asymmetrical bis-N-heterocyclic carbene ligands with methylene or ethylene linker groups. This synthetic approach is versatile and allows for the synthesis of heterobimetallic complexes bearing asymmetrical ligands that differ in the nature of the NHC wingtip substituents (dimethyl, diethyl or ethyl-methyl) and for the selective placement of the different metal ions. The synthesised complexes were characterised using 1H and 13C NMR spectroscopy and high resolution mass spectrometry (HR-MS) and in the case of complexes 4a, 5b and 8b by X-ray crystallography.

Diversity in the intrinsic apoptosis pathway of nematodes.

Early studies of the free-living nematode C. elegans informed us how BCL-2-regulated apoptosis in humans is regulated. However, subsequent studies showed C.

Histidine-Rich Defensins from the and Are Antifungal and Metal Binding Proteins.

Plant defensins are best known for their antifungal activity and contribution to the plant immune system. The defining feature of plant defensins is their three-dimensional structure known as the cysteine stabilized alpha-beta motif. This protein fold is remarkably tolerant to sequence variation with only the eight cysteines that contribute to the stabilizing disulfide bonds absolutely conserved across the family.

Structural insight into tanapoxvirus-mediated inhibition of apoptosis.

Premature programmed cell death or apoptosis of cells is a strategy utilized by multicellular organisms to counter microbial threats. Tanapoxvirus (TANV) is a large double-stranded DNA virus belonging to the poxviridae that causes mild monkeypox-like infections in humans and primates. TANV encodes for a putative apoptosis inhibitory protein 16L.

Heparanase: Cloning, Function and Regulation.

In 2019, we mark the 20th anniversary of the cloning of the human heparanase gene. Heparanase remains the only known enzyme to cleave heparan sulfate, which is an abundant component of the extracellular matrix. Thus, elucidating the mechanisms underlying heparanase expression and activity is critical to understanding its role in healthy and pathological settings.

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 Cu -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).

Identification of two dihydrodipicolinate synthase isoforms from Pseudomonas aeruginosa that differ in allosteric regulation.

Pseudomonas aeruginosa is one of the leading causes of nosocomial infections, accounting for 10% of all hospital-acquired infections. Current antibiotics against P. aeruginosa are becoming increasingly ineffective due to the exponential rise in drug resistance.