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Genomics-driven discovery of novel drug leads in underexplored microorganisms

Segurado Luchsinger, Alejandro Eulogio (2021) MOBM02 20211
Degree Projects in Molecular Biology
Popular Abstract
Underexplored Gram (-) bacteria as a new source of natural products.

Microorganisms produce an impressive array of structurally diverse and complex natural products with industrially-important properties. Microbial natural products therefore continue to be an important source of clinical drug candidates. While natural products from a few soil Gram (+) bacteria, together with their biosynthetic pathways, have been studied extensively over the past few decades, very little is known about the breath of bioactive natural products secreted by Gram (-) bacteria.
In recent years, genome sequencing has identified thousands of unique biosynthetic gene clusters (BGCs) producing uncharacterized natural products with therapeutic potential. Due to... (More)
Underexplored Gram (-) bacteria as a new source of natural products.

Microorganisms produce an impressive array of structurally diverse and complex natural products with industrially-important properties. Microbial natural products therefore continue to be an important source of clinical drug candidates. While natural products from a few soil Gram (+) bacteria, together with their biosynthetic pathways, have been studied extensively over the past few decades, very little is known about the breath of bioactive natural products secreted by Gram (-) bacteria.
In recent years, genome sequencing has identified thousands of unique biosynthetic gene clusters (BGCs) producing uncharacterized natural products with therapeutic potential. Due to their huge diversity and versatility, they could play a very important role in the drug discovery industry for the coming years. Among the Gram (-) bacteria, the Burkholderiales in particular have proven to be a rich source of natural products with different functions that can provide interesting new leads.
This project analysed the biosynthetic potential of three Burkholderiales species (Burkholderia singularis, Caballeronia choica and Caballeronia cordobensis) following a genome mining strategy and aimed to discover, identify, and characterize novel bioactive natural products. To do so, major biosynthetic genes within selected BGCs were inactivated and the metabolic profiles from wild type and knocked out strains were compared under an OSMAC (one strain many compounds) approach. Additionally, a triparental mating/ conjugation protocol for transforming Caballeronia species was stablished, allowing us to inactivate genes within the genome of C. choica and C. cordobensis.

Combinatorial Bottom-up/Top-down approaches prove to be good drug discovery strategies.
After analyzing the genomes from B. singularis, C. choica and C. cordobensis with AntiSMASH and Interpro a total of four biosynthetic gene clusters were selected. Predictions showed an iterative polyketide synthase I cluster in B. singularis, a polyketide-non ribosomal peptide hybrid synthase cluster in C. choica and two non-ribosomal peptide synthase clusters in C. cordobensis. In order to corroborate these results an insertional inactivation of the core biosynthetic genes of each cluster was performed and the metabolic profiles of the wild type and mutant strains were compared to find possible candidates. In addition, by varying the carbon source in the growth media, many silent BGCs were activated and a prime candidate for isolation and characterization were selected. Alternatively, preliminary antimicrobial bioactivity assays showed an interesting lead in B. singularis with antibiotic activity against methicillin resistant S. aureus (MRSA). Although more work is needed to characterize all the interesting leads we came across; it is obvious that there is much potential in these bacterial strains from which we might benefit from.

Master’s Degree Project in Molecular Biology, 30 credits 2021
Department of Biology, Lund University
Advisor: Joleen Masschelein
Biomolecular Discovery and Engineering unit
Department of Biology, Faculty of Science (KU Leuven)
Kasteelpark Arenberg 31 – Box 2438
3001 (Leuven, Belgium) (Less)
Please use this url to cite or link to this publication:
author
Segurado Luchsinger, Alejandro Eulogio
supervisor
organization
course
MOBM02 20211
year
type
H2 - Master's Degree (Two Years)
subject
language
English
id
9060511
date added to LUP
2021-07-02 09:53:30
date last changed
2021-07-02 09:53:30
@misc{9060511,
  author       = {{Segurado Luchsinger, Alejandro Eulogio}},
  language     = {{eng}},
  note         = {{Student Paper}},
  title        = {{Genomics-driven discovery of novel drug leads in underexplored microorganisms}},
  year         = {{2021}},
}