JCJC SVSE 8 - JCJC - SVSE 8 - Biochime, biologie moléculaire et structurale

Genome mining of Trojan horse antibiotics: a combined chemical, biosynthetical and enzymological study – GenoTrojan

Trojan horse antibiotics : new avenues for combating bacterial infections

Identification, biosynthesis and engineering of Trojan horse antibiotics from bacteria

Chasing the right molecules

Bacterial resistance to existing antibiotics remains a major health concern. There is an urgent need for discovery of novel antibiotics. Some Bacteria utilise an elegant “Trojan horse“ strategy to fight against their competitors. They secrete small molecules which possess structural motifs in disguise that facilitate their uptake by the enemy cells and toxic moieties. Once inside the cell, the disguise is removed and the toxic part targets a specific cellular function. This strategy is a valuable inspiration for new antibiotic development. The modularity of the disguise and toxic parts provides opportunities for combination to generate novel molecules. The project aims at identifying new “Trojan horse” molecules from bacteria and understanding how they are made in bacteria. The knowledge of their biosynthesis will lead to generation of chimeric molecules with new antibiotic activities by a combinatorial approach.

Expanding bacterial genome sequences have revealed that bacteria harbour a great potential to synthesize diverse molecules with pharmaceutical values. Based on the current knowledge of the genes involved in the biosynthesis of agrocin K84, a natural Trojan horse antibiotic produced by Agrobacterium, similar but not identical gene clusters were identified from bacteria in various ecological niches. These include bacteria involved in a multipartite symbiosis and some soil bacteria. Guided by such genomic analysis, a combination of microbiology, small molecule chemistry, protein biochemistry and molecular biology will be applied to elucidate the identity of putative compounds, to characterise and engineer the biosynthetic enzymes and to apply the biosynthetic machineries for generation of non-natural Trojan horse antibiotics.

As a start, we have modified genetically selected bacteria by deleting essential genes involved in the synthesis of the putative compounds. These mutants will be cultured and their metabolite profiles will be compared to that of the wild-type strain. Moreover, we have constructed genomic DNA libraries, which sets the stage for expression of the gene cluster in a heterologous host such as Escherichia coli.

The expected compounds will find potential applications in antibiotics development. The elucidated biosynthetic machineries will not only reveal novel enzymatic chemistry, but also have applications in chemo-enzymo synthesis of complex structures.

There is not yet scientific production at this stage.

“Trojan horse” antibiotics employ an elegant strategy to defeat sensitive bacteria. They possess a structural motif in disguise which helps to traverse cell membranes, and a toxic part that targets specific cellular function once the disguise is removed. This strategy is a useful inspiration for antibiotic development. Intrigued by the rare occurrence of such antibiotics in Nature, this proposal will use a genome mining strategy to identify new metabolites of this type from bacteria, particularly molecules targeting aminoacyl-tRNA synthetases. Their molecular basis of biosynthesis will be studied, aimed at applying such enzymatic machineries to generate analogs that may have new antibacterial activity.

Project coordinator

Madame Yanyan Li (CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION REGIONALE ILE-DE-FRANCE SECTEUR EST) – yanyanli@mnhn.fr

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

CNRS DR PARIS B CNRS DR PARIS B
CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION REGIONALE ILE-DE-FRANCE SECTEUR EST

Help of the ANR 119,000 euros
Beginning and duration of the scientific project: - 36 Months

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