Closthioamide: An Unprecedented Polythioamide Antibiotic from the Strictly Anaerobic Bacterium Clostridium cellulolyticum

Abstract

Choose sulfur in an oxygen‐free world: Closthioamide (1) was isolated from the anaerobe Clostridium cellulolyticum (see SEM image) after the induction of its biosynthesis with an aqueous soil extract. An unprecedented type of symmetrical natural product in which all building blocks are connected through thioamide linkages, 1 is active against multiresistant staphylococci. It is the only known secondary metabolite from a strictly anaerobic bacterium.

Methanobactin and the Link between Copper and Bacterial Methane Oxidation

“…For instance, Clostridium cellulolyticum produces a copper-binding secondary metabolite, closthioamide, with a molecular mass similar to that of mbs (158)(159)(160), and like mbs, closthioamide has thioamide groups, will reduce Cu 2ϩ to Cu 1ϩ , and has a high Cu 1ϩ binding affinity (Ͼ10 15 M Ϫ1 ). Closthioamine will also test positive with the copper-chrome azural S (Cu-CAS) assay, a liquid or plate assay used to screen for mb production (138,149,161).…”

“…Pyrazinedione rings are even more uncommon and have been detected only in the non-amino-acidcontaining molecules selerominol (167) and flutamide (168) from fungi. The presence of thioamide groups in natural products is also rare and has been identified only in closthioamide from Clostridium cellulolyticum (153,160) and thioviridamide from Streptomyces olivoviridis (169,170). Although rare, O-sulfonation of Ser or Thr has been reported in eukaryotic proteins (171), but to our knowledge, mb is the only bacterial peptide that contains this posttranslational modification and is ribosomally produced, as described below.…”

Antibiotics from neglected bacterial sources

“…In an attempt to harness the biosynthetic potential of Clostridium cellulolyticum cultures were subjected to >30 stress conditions including heat shock, heavy metal and antibiotic stress (Fig. 4) (Lincke et al, 2010). Yet only upon the addition of an aqueous soil extract to C. cellulolyticum cultures a new compound, named closthioamide, was detected (Lincke et al, 2010).…”

“…4) (Lincke et al, 2010). Yet only upon the addition of an aqueous soil extract to C. cellulolyticum cultures a new compound, named closthioamide, was detected (Lincke et al, 2010). Closthioamide has an unusual symmetric structure and is very rich in thioamide moieties, which are rarely found in nature.…”

Anaerobic bacteria as producers of antibiotics

“…Yet, not a single gene cluster could be linked to a metabolite. In C. cellulolyticum, a group of unusual new polythioamide metabolites, the closthioamides (1-8), has already been identified (Behnken et al 2012;Lincke et al 2010), and their biosynthetic pathway is now under investigation. The high antibiotic activity and structural novelty of closthioamide (1) suggests that more unique drug leads can be unearthed from anaerobes-thus complementing the biosynthetic potential of established aerobic antibiotic producers.…”