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

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.

Dark, rare and inspirational microbial matter in the extremobiosphere: 16 000 m of bioprospecting campaigns

“…abyssomicins These spirotetronate polyketides, first isolated from the deep sea Verrucosispora maris AB-18-032 T , and detected by assay-guided screening possess a unique chemical scaffold and antibacterial mode of action [5]; they are among those dubbed 'inspirational natural products' by Nicolaou [38]. Subsequently members of this chemical class have been found in species of Streptomyces and currently 32 natural abyssomicins and many chemically synthesized analogues have been described [39]. Following the defining of anti-Gram-positive bacteria activities [including methicillin-and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA)], particular abyssomicins have been shown to express anti-TB and anticancer properties, to reactivate latent human immunodeficiency virus (HIV), induce HIV replication, and to have anti-HIV action.…”

“…To our knowledge, none of these diverse abyssomicin attributes has yet led to pharmaceutical development but the recent resurgence of interest coupled with an increasing ability to improve drug efficacy and lower toxicity via medicinal chemistry holds promise for such prodrug development. The excellent review of Sadaka et al [39] elaborates these and related aspects of the abyssomicin family.…”

Out of the abyss: Genome and metagenome mining reveals unexpected environmental distribution of abyssomicins

“…In fact, the biological activity of abyssomicins includes antimicrobial activities against Grampositive bacteria and Mycobacteria (Freundlich et al, 2010;Riedlinger et al, 2004). Other biological activities discovered so far are antitumor properties, latent human immunodeficiency virus (HIV) reactivator, anti-HIV and HIV replication inducer properties (Sadaka et al, 2018). The wide diversity of abyssomicin BGCs that we have found through genome mining suggests that a plethora of abyssomicin-like molecules remains unknown.…”

“…Until today, only nine bacterial strains have been reported to produce abyssomicins (Table S1). From these strains, 37 abyssomicins with differences at structural and bioactivity levels have been characterized (Sadaka et al, 2018). With the aim of studying the distribution of those microorganisms capable of producing new abyssomicin molecules, we have analysed in silico an extensive diversity of metagenomes and genomes.…”

“…The narrow number of bacterial strains identified so far as abyssomycin producers is in contrast with the structural diversity of these molecules. In fact, this family has as many as 37 members classified to date as type I or type II abyssomicins, depending on their structure, where the type I family includes abyssomicins B-E, G, H, J-L and atropabyssomicin C, and type II abyssomicins are the enantiomeric counterparts of the type I compounds (Sadaka et al, 2018).…”