Biosynthesis of Diverse Antimicrobial and Antiproliferative Acyloins in Anaerobic Bacteria

Abstract

Metabolic profiling and genome mining revealed that anaerobic bacteria have the potential to produce acyloin natural products. In addition to sattazolin A and B, three new sattazolin congeners and a novel acyloin named clostrocyloin were isolated from three strains of Clostridium beijerinckii, a bacterium used for industrial solvent production. Bioactivity profiling showed that the sattazolin derivatives possess antimicrobial activities against mycobacteria and pseudomonads with only low cytotoxicity. Clostrocyloin was found to be mainly active against fungi. The thiamine diphosphate (ThDP)dependent sattazolin-producing synthase was identified in silico and characterized both in vivo and in in vitro enzyme assays. A related acyloin synthase from the clostrocyloin producer was shown to be responsible for the production of the acyloin core of clostrocyloin. The biotransformation experiments provided first insights into the substrate scope of the clostrocyloin synthase and revealed biosynthetic intermediates.

Induction of antibiotic specialized metabolism by co‐culturing in a collection of phyllosphere bacteria

“…Compounds 2,3,4 and 5 have been discovered and isolated from Xenorhabdus spp. (Proschak et al, 2014), and biosynthesised recently (Park et al, 2014;Schieferdecker et al, 2019). Compound 1 is a new natural product active on A. baumannii LMG 10520.…”

“…Indole containing xenocyloins and the phenyl containing sattabacins have been shown to be bioactive in the laboratory. For example, xenocyloins were active against the fungi Cryptococcus neoformans, Botrytis cinerea and Phytophthora infestans (Paul et al, 1981;Li et al, 1995) and sattazolins isolated from Clostridium were active against S. aureus or Mycobacterium vaccae (Schieferdecker et al, 2019). Interestingly, sattabacins showed antiviral activity against Herpes simplex virus (Lampis et al, 1995).…”

“…The CDS with locus tag GC101_RS07275 lies within a putative operon with a gene encoding a carboxymuconolactone decarboxylase homologue (GC101_RS07280) and a 3-oxoacyl ACP synthase III homologue (GC101_RS07290). These functions are also encoded in the xenocyloin BGC (MIBIG accession number BGC0000189) and are hypothesized to catalyse the decarboxylation of the biosynthetic intermediate and O-acylation respectively (Proschak et al, 2014;Schieferdecker et al, 2019) (Fig. 5).…”

Induced Production, Synthesis, and Immunomodulatory Action of Clostrisulfone, a Diarylsulfone from Clostridium acetobutylicum

“…However, in most cases the gene clusters are silent and need to be activated by means of particular stimuli. Several genetic and chemical approaches to triggering biosynthesis [5] have been applied to clostridia, [3a, 6] A range of antibiotics, such as closthioamides, [3a, 7] clostrubins, [8] clostrindoline, [9] antibacterial acyloins, [10] and a new lipopeptide [11] have been isolated from various clostridia. Mining the genome sequence of C. acetobutylicum [12] pointed to a high biosynthetic potential [4] .…”

Reconstitution of polythioamide antibiotic backbone formation reveals unusual thiotemplated assembly strategy

“…CTA is a DNA gyrase-targeting antibiotic with potent inhibitory activity against clinically important bacterial pathogens, including drug-resistant strains (7)(8)(9)(10), and is a rare example of a thioamidated NRP (11,12). This unusual copper chelating NRP (13) is produced by Ruminiclostridium cellulolyticum DSM 5812 (7,14) and is one of only a handful of natural products isolated from anaerobic bacteria (15)(16)(17). Knockout studies and in vitro biochemical assays led to the identification of the enzymes responsible for sulfur insertion and late-stage intermediate dimerization (Fig.…”