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Carbohydrate scaffolds as glycosyltransferase inhibitors with in vivo antibacterial activity.

Zuegg J, Muldoon C, Adamson G, McKeveney D, Le Thanh G, Premraj R, Becker B, Cheng M, Elliott AG, Huang JX, Butler MS, Bajaj M, Seifert J, Singh L, Galley NF, Roper DI, Lloyd AJ, Dowson CG, Cheng TJ, Cheng WC, Demon D, Meyer E, Meutermans W, Cooper MA - Nat Commun (2015)

Bottom Line: 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.This approach based on non-planar carbohydrate scaffolds provides a new opportunity to develop new antibiotics with low propensity for resistance induction.

View Article: PubMed Central - PubMed

Affiliation: 1] Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia [2] Alchemia Ltd, PO Box 4851, Eight Mile Plains, Brisbane, Queensland 4113, Australia.

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.

No MeSH data available.


Related in: MedlinePlus

Overview of PG cell wall synthesis and inhibitors.(a) PG synthesis in bacteria from lipid II with subsequent GT and TP catalysis, with A: L-Ala, a: D-Ala, e: D-iGln, X: either D-Lys(Ala5) in case of Staphylococcus, or mDap in case of Bacillus. (b) Structure and in vitro activity of moenomycin A, indicating the different moieties with A to G. (c) Structure and in vitro activity of moenomycin's disaccharide degradation product.
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f1: Overview of PG cell wall synthesis and inhibitors.(a) PG synthesis in bacteria from lipid II with subsequent GT and TP catalysis, with A: L-Ala, a: D-Ala, e: D-iGln, X: either D-Lys(Ala5) in case of Staphylococcus, or mDap in case of Bacillus. (b) Structure and in vitro activity of moenomycin A, indicating the different moieties with A to G. (c) Structure and in vitro activity of moenomycin's disaccharide degradation product.

Mentions: Peptidoglycan glycosyltransferases (GT) and transpeptidases (TP) are two key enzymes in the final steps of peptidoglycan (PG) biosynthesis essential for bacterial cell wall integrity and stability. GTs catalyse the polymerization of lipid II disaccharide units, forming a long chain of alternating β-1,4-linked N-acetylglucosamines and N-acetylmuramic acid, leading to a linear glycan chain and the release of undecaprenyl-pyrophosphate carrier123. These carbohydrate chains are further crosslinked by TP enzymes, forming linkages between the peptide chain and the D-alanine of a neighboring unit (Fig. 1). GT and TP enzymes are unique to bacteria and are expressed either as individual domains, monofunctional GT (MGT) and penicillin-binding proteins (PBP), respectively or as bifunctional proteins that possess both GT and TP domains (class A PBP)45.


Carbohydrate scaffolds as glycosyltransferase inhibitors with in vivo antibacterial activity.

Zuegg J, Muldoon C, Adamson G, McKeveney D, Le Thanh G, Premraj R, Becker B, Cheng M, Elliott AG, Huang JX, Butler MS, Bajaj M, Seifert J, Singh L, Galley NF, Roper DI, Lloyd AJ, Dowson CG, Cheng TJ, Cheng WC, Demon D, Meyer E, Meutermans W, Cooper MA - Nat Commun (2015)

Overview of PG cell wall synthesis and inhibitors.(a) PG synthesis in bacteria from lipid II with subsequent GT and TP catalysis, with A: L-Ala, a: D-Ala, e: D-iGln, X: either D-Lys(Ala5) in case of Staphylococcus, or mDap in case of Bacillus. (b) Structure and in vitro activity of moenomycin A, indicating the different moieties with A to G. (c) Structure and in vitro activity of moenomycin's disaccharide degradation product.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4530474&req=5

f1: Overview of PG cell wall synthesis and inhibitors.(a) PG synthesis in bacteria from lipid II with subsequent GT and TP catalysis, with A: L-Ala, a: D-Ala, e: D-iGln, X: either D-Lys(Ala5) in case of Staphylococcus, or mDap in case of Bacillus. (b) Structure and in vitro activity of moenomycin A, indicating the different moieties with A to G. (c) Structure and in vitro activity of moenomycin's disaccharide degradation product.
Mentions: Peptidoglycan glycosyltransferases (GT) and transpeptidases (TP) are two key enzymes in the final steps of peptidoglycan (PG) biosynthesis essential for bacterial cell wall integrity and stability. GTs catalyse the polymerization of lipid II disaccharide units, forming a long chain of alternating β-1,4-linked N-acetylglucosamines and N-acetylmuramic acid, leading to a linear glycan chain and the release of undecaprenyl-pyrophosphate carrier123. These carbohydrate chains are further crosslinked by TP enzymes, forming linkages between the peptide chain and the D-alanine of a neighboring unit (Fig. 1). GT and TP enzymes are unique to bacteria and are expressed either as individual domains, monofunctional GT (MGT) and penicillin-binding proteins (PBP), respectively or as bifunctional proteins that possess both GT and TP domains (class A PBP)45.

Bottom Line: 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.This approach based on non-planar carbohydrate scaffolds provides a new opportunity to develop new antibiotics with low propensity for resistance induction.

View Article: PubMed Central - PubMed

Affiliation: 1] Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia [2] Alchemia Ltd, PO Box 4851, Eight Mile Plains, Brisbane, Queensland 4113, Australia.

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.

No MeSH data available.


Related in: MedlinePlus