Biology subjects

Bailey, A. M.

Publications and source records attributed to Bailey, A. M..

3 recordsLinked to original sources

bioRxiv2022

Biosynthesis of pleuromutilin congeners using an Aspergillus oryzae expression platform

Pleuromutilin is an antibiotic diterpenoid made by Clitopilus passeckerianus and related fungi, and it is the progenitor of a growing class of semi-synthetic antibiotics used in veterinary and human medicine. To harness the biotechnological potential of this natural product class, a full understanding of its biosynthetic pathway is essential. Previously, a linear pathway for pleuromutilin biosynthesis was established. Here we report two shunt pathways involving Pl-sdr and Pl-atf that were identified through the rational heterologous expression of combinations of pleuromutilin biosynthetic genes in Aspergillus oryzae. Three novel pleuromutilin congeners were isolated, and their antimicrobial activity was investigated, alongside that of an additional derivative produced through a semi-synthetic approach. It was observed that the absence of substituents - C-3 keto, C-11 hydroxy or C-21 keto - from the pleuromutilin core affected the antibacterial activity of pleuromutilin congeners. This study expands our knowledge on the biosynthesis of pleuromutilin and provides avenues for the development of novel pleuromutilin analogues by combining synthetic biology and synthetic chemistry.

microbiology↗

bioRxiv2021

In silico analyses of maleidride biosynthetic gene clusters

Maleidrides are a family of structurally related fungal natural products, many of which possess diverse, potent bioactivities. Previous identification of several maleidride biosynthetic gene clusters, and subsequent experimental work, has determined the core set of genes required to construct the characteristic medium-sized alicyclic ring with maleic anhydride moieties. Through genome mining, this work has used these core genes to discover ten entirely novel maleidride biosynthetic gene clusters, amongst both publicly available genomes, and encoded within the genome of the previously un-sequenced epiheveadride producer Wicklowia aquatica CBS125634. We have undertaken phylogenetic analyses and comparative bioinformatics on all known and putative maleidride biosynthetic gene clusters to gain further insights regarding these unique biosynthetic pathways.

bioinformatics↗

bioRxiv2020

Further biochemical profiling of Hypholoma fasciculare metabolome reveals its chemo-genetic diversity

There is a desperate need in continuing the search for natural products with novel mechanism to battle the constant increase of microbial drug resistance. Previously mushroom forming fungi were neglected as a source of novel antibiotics, due to the difficulties associated with their culture preparation and genetic tractability. However, modern fungal molecular and synthetic biology tools, renewed the interest in exploring mushroom fungi for novel therapeutics. The aim of this study was to have a comprehensive picture of nine basidiomycetes secondary metabolites (SM), screen their biological and chemical properties to describe the genetic pathways associated with their production. H. fasciculare revealed to be highly active antagonistic species, with antimicrobial activity against three different microorganisms - Bacillus subtilis, Escherichia coli and Saccharomyces cerevisiae-. Extensive genomic comparison and chemical analysis using analytical chromatography, led to the characterisation of more than 15 variant biosynthetic gene clusters and the first identification of a potent antibacterial metabolite-3, 5-dichloromethoxy benzoic acid (3, 5-D)-in this species, for which a biosynthetic gene cluster was predicted. This work demonstrates the great potential of mushroom forming fungi as a reservoir of bioactive natural products which are currently unexplored, and that access to their genomic data and structural diversity natural products via utilizing modern computational analysis and efficient chemical methods, could accelerate the development and applications of such distinct molecules in both pharmaceutical and agrochemical industry.

molecular biology↗