AbstractAntibiotics have become central to public health. However, our misuse of these
compounds has accelerated an antimicrobial resistance crisis and caused an urgent need to discover new compounds. To overcome this problem, one strategy focuses on utilizing the vast microbial diversity that remains unexplored and study their potential to produce novel antibiotics. In line with that, this project focuses on a set of strains (CG885, CG893 and CG926) isolated from a páramo, a high-altitude ecosystem, in the northern Andes of South America.
Bioassays, phylogenetic analyses, and genome mining suggest the strain CG926 is
the most promising. It was found to be a new species (Streptomyces paramonensis), to harbour an 8.5 Mb genome, which contains around 25 biosynthetic gene clusters (BGCs) potentially related to bioactive compounds and to have the strongest antimicrobial activity against Gram-positive and Gram-negative bacteria.
To further study this novel strain, we used the heterologous host S. coelicolor M1146 to successfully express the cluster Hyb-5, which is predicted to encode a novel antimicrobial. The 70-kb BGC comprises 52 open reading frames including two genes coding for a Non-Ribosomal Protein Synthase (NRPS) and one encoding a type-1 Polyketide Synthase (PKS). It also contains a stravidin cluster, svnA-N, and two flanking streptavidin genes that have been linked before with an antimicrobial complex that targets biotin.
Antimicrobial assays and chemical analyses in UHPLC-HRMS were also performed
to explore the features of this potentially novel bioactive compound. Ethyl acetate
extracts of the recombinant S. coelicolor M1146 revealed antimicrobial activity against Gram-positive and Gram-negative bacteria and chemical features that have no match with any known compounds to date. Overall, these results show that studying the microbial diversity of underexplored environments is a potentially fruitful strategy for finding novel antibiotics and to contribute to the fight against antimicrobial resistance.
|Date of Award||28 Apr 2023|
|Supervisor||LORENA FERNANDEZ-MARTINEZ (Director of Studies), PAUL ASHTON (Supervisor) & MARIA MERCEDES ZAMBRANO (Supervisor)|
- antimicrobial resistance
- genome mining
- heterologous expression