Declan McKeveney

Bio: Declan McKeveney is an academic researcher from Griffith University. The author has contributed to research in topics: Hydrogen bond & Nucleophilic substitution. The author has an hindex of 4, co-authored 7 publications receiving 141 citations.

Carbohydrate scaffolds as glycosyltransferase inhibitors with in vivo antibacterial activity

Abstract: The rapid rise of multi-drug-resistant bacteria is a global healthcare crisis, and new antibiotics are urgently required, especially those with modes of action that have low-resistance potential. One promising lead is the liposaccharide antibiotic moenomycin that inhibits bacterial glycosyltransferases, which are essential for peptidoglycan polymerization, while displaying a low rate of resistance. Unfortunately, the lipophilicity of moenomycin leads to unfavourable pharmacokinetic properties that render it unsuitable for systemic administration. In this study, we show that using moenomycin and other glycosyltransferase inhibitors as templates, we were able to synthesize compound libraries based on novel pyranose scaffold chemistry, with moenomycin-like activity, but with improved drug-like properties. The novel compounds exhibit in vitro inhibition comparable to moenomycin, with low toxicity and good efficacy in several in vivo models of infection. This approach based on non-planar carbohydrate scaffolds provides a new opportunity to develop new antibiotics with low propensity for resistance induction.

A versatile synthetic approach toward diversity libraries using monosaccharide scaffolds.

Abstract: The pyranose scaffold is unique in its ability to position pharmacophore substituents in various ways in 3D space, and unique pharmacophore scanning libraries could be envisaged that focus on scanning topography rather than diversity in the type of substituents. Approaches have been described that make use of amine and acid functionalities on the pyranose scaffolds to append substituents, and this has enabled the generation of libraries of significant structural diversity. Our general aim was to generate libraries of pyranose-based drug-like mimetics, where the substituents are held close to the scaffold, in order to obtain molecules with better defined positions for the pharmacophore substituents. Here we describe the development of a versatile synthetic route toward peptide mimetics build on 2-amino pyranose scaffolds. The method allows introduction of a wide range of substituent types, it is regio- and stereospecific, and the later diversity steps are performed on solid phase. Further, the same process was applied on glucose and allose scaffolds, in the exemplified cases, and is likely adaptable to other pyranose building blocks. The methods developed in this work give access to molecules that position the three selected binding elements in various 3D orientations on a pyranose scaffold and have been applied for the production of a systematically diverse library of several hundred monosaccharide-based mimetics.

Biologically Active Compounds with Anti-Angiogenic Properties

Abstract: A method for inhibiting angiogenesis in a subject comprising administering to the subject at least one compound of General Formula (I), wherein the ring or any chiral center(s) may be of any configuration; Z is sulphur, oxygen, CH2, C(O), C(O)HN, NH, NRA or hydrogen, in the case where Z is hydrogen then R1 is not present, RA is selected from the set defined for R1 to R5, X and X′ are independently oxygen or nitrogen providing that at least one X of General Formula (I) is nitrogen, X or X′ may also combine independently with one of R1 to R5 to form an azide, R1 to R5 are independently selected from the following definition which includes but is not limited to H or an alkyl, acyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl substituent of 1 to 20 atoms, which is optionally substituted, and can be branched or linear, and R6 and R7 are hydrogen, or may combine to form a carbonyl function.

Structural insight into the transglycosylation step of bacterial cell-wall biosynthesis.

Abstract: Peptidoglycan glycosyltransferases (GTs) catalyze the polymerization step of cell-wall biosynthesis, are membrane-bound, and are highly conserved across all bacteria. Long considered the “holy grail” of antibiotic research, they represent an essential and easily accessible drug target for antibiotic-resistant bacteria, including methicillin-resistant Staphylococcus aureus . We have determined the 2.8 angstrom structure of a bifunctional cell-wall cross-linking enzyme, including its transpeptidase and GT domains, both unliganded and complexed with the substrate analog moenomycin. The peptidoglycan GTs adopt a fold distinct from those of other GT classes. The structures give insight into critical features of the catalytic mechanism and key interactions required for enzyme inhibition.

Antibacterial discovery and development--the failure of success?

Abstract: A combination of approaches and compounds-many of which failed to yield immediate results in the past-will ultimately prove invaluable to the drug industry in the ongoing battle against infectious disease.

Lipid Intermediates in the Biosynthesis of Bacterial Peptidoglycan

Abstract: Summary: This review is an attempt to bring together and critically evaluate the now-abundant but dispersed data concerning the lipid intermediates of the biosynthesis of bacterial peptidoglycan. Lipid I, lipid II, and their modified forms play a key role not only as the specific link between the intracellular synthesis of the peptidoglycan monomer unit and the extracytoplasmic polymerization reactions but also in the attachment of proteins to the bacterial cell wall and in the mechanisms of action of antibiotics with which they form specific complexes. The survey deals first with their detection, purification, structure, and preparation by chemical and enzymatic methods. The recent important advances in the study of transferases MraY and MurG, responsible for the formation of lipids I and II, are reported. Various modifications undergone by lipids I and II are described, especially those occurring in gram-positive organisms. The following section concerns the cellular location of the lipid intermediates and the translocation of lipid II across the cytoplasmic membrane. The great efforts made since 2000 in the study of the glycosyltransferases catalyzing the glycan chain formation with lipid II or analogues are analyzed in detail. Finally, examples of antibiotics forming complexes with the lipid intermediates are presented.

Crystal structure of the membrane-bound bifunctional transglycosylase PBP1b from Escherichia coli

Abstract: Drug-resistant bacteria have caused serious medical problems in recent years, and the need for new antibacterial agents is undisputed. Transglycosylase, a multidomain membrane protein essential for cell wall synthesis, is an excellent target for the development of new antibiotics. Here, we determined the X-ray crystal structure of the bifunctional transglycosylase penicillin-binding protein 1b (PBP1b) from Escherichia coli in complex with its inhibitor moenomycin to 2.16-A resolution. In addition to the transglycosylase and transpeptidase domains, our structure provides a complete visualization of this important antibacterial target, and reveals a domain for protein–protein interaction and a transmembrane helix domain essential for substrate binding, enzymatic activity, and membrane orientation.

Progress in the pursuit of therapeutic adenosine receptor antagonists.

Abstract: Ever since the discovery of the hypotensive and bradycardiac effects of adenosine, adenosine receptors continue to represent promising drug targets. First, this is due to the fact that the receptors are expressed in a large variety of tissues. In particular, the actions of adenosine (or methylxanthine antagonists) in the central nervous system, in the circulation, on immune cells, and on other tissues can be beneficial in certain disorders. Second, there exists a large number of ligands, which have been generated by introducing several modifications in the structure of the lead compounds (adenosine and methylxanthine), some of them highly specific. Four adenosine receptor subtypes (A1, A2A, A2B, and A3) have been cloned and pharmacologically characterized, all of which are G protein-coupled receptors. Adenosine receptors can be distinguished according to their preferred mechanism of signal transduction: A1 and A3 receptors interact with pertussis toxin-sensitive G proteins of the Gi and Go family; the canonical signaling mechanism of the A2A and of the A2B receptors is stimulation of adenylyl cyclase via Gs proteins. In addition to the coupling to adenylyl cyclase, all four subtypes may positively couple to phospholipase C via different G protein subunits. The development of new ligands, in particular, potent and selective antagonists, for all subtypes of adenosine receptors has so far been directed by traditional medicinal chemistry. The availability of genetic information promises to facilitate understanding of the drug-receptor interaction leading to the rational design of a potentially therapeutically important class of drugs. Moreover, molecular modeling may further rationalize observed interactions between the receptors and their ligands. In this review, we will summarize the most relevant progress in developing new therapeutic adenosine receptor antagonists.