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Molecules 2018, 23(6), 1371; https://doi.org/10.3390/molecules23061371

Review on Abyssomicins: Inhibitors of the Chorismate Pathway and Folate Biosynthesis

1
Department of Veterinary and Animal Sciences, University of Copenhagen, Stigboejlen 41870, Frederiksberg C, Denmark
2
Department of Pharmacology and Toxicology, Michigan State University, 220 Trowbridge Road, East Lansing, MI 48824, USA
3
Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2100, Copenhagen, Denmark
4
Zoetis Global Therapeutics Research, 333 Portage Street, Kalamazoo, MI 49007, USA
*
Authors to whom correspondence should be addressed.
Received: 6 May 2018 / Revised: 30 May 2018 / Accepted: 4 June 2018 / Published: 6 June 2018
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Abstract

Antifolates targeting folate biosynthesis within the shikimate-chorismate-folate metabolic pathway are ideal and selective antimicrobials, since higher eukaryotes lack this pathway and rely on an exogenous source of folate. Resistance to the available antifolates, inhibiting the folate pathway, underlines the need for novel antibiotic scaffolds and molecular targets. While para-aminobenzoic acid synthesis within the chorismate pathway constitutes a novel molecular target for antifolates, abyssomicins are its first known natural inhibitors. This review describes the abyssomicin family, a novel spirotetronate polyketide Class I antimicrobial. It summarizes synthetic and biological studies, structural, biosynthetic, and biological properties of the abyssomicin family members. This paper aims to explain their molecular target, mechanism of action, structure–activity relationship, and to explore their biological and pharmacological potential. Thirty-two natural abyssomicins and numerous synthetic analogues have been reported. The biological activity of abyssomicins includes their antimicrobial activity against Gram-positive bacteria and mycobacteria, antitumor properties, latent human immunodeficiency virus (HIV) reactivator, anti-HIV and HIV replication inducer properties. Their antimalarial properties have not been explored yet. Future analoging programs using the structure–activity relationship data and synthetic approaches may provide a novel abyssomicin structure that is active and devoid of cytotoxicity. Abyssomicin J and atrop-o-benzyl-desmethylabyssomicin C constitute promising candidates for such programs. View Full-Text
Keywords: antifolate; para-aminobenzoic acid; chorismate; resistance; spirotetronate; antibiotic; sulfonamides; prodrug; analoging antifolate; para-aminobenzoic acid; chorismate; resistance; spirotetronate; antibiotic; sulfonamides; prodrug; analoging
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Sadaka, C.; Ellsworth, E.; Hansen, P.R.; Ewin, R.; Damborg, P.; Watts, J.L. Review on Abyssomicins: Inhibitors of the Chorismate Pathway and Folate Biosynthesis. Molecules 2018, 23, 1371.

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