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Erasing the superintegron to understand the role of chromosomal integrons in bacterial evolution

Objective

Integrons are genetic platforms that enhance bacterial evolvability through the acquisition and stockpiling of new genes encoded in mobile elements named cassettes. They are found in the chromosomes of environmental bacteria but some have acquired mobility through their association to transposons and conjugative plasmids. These mobile integrons (MI) caused the unexpected rise of multidrug resistance that is now a major threat to modern medicine, and are good proof of the adaptive power of integrons. Class 1 integrons are the most relevant MI and the major experimental model. Yet little is known about the hundreds of sedentary chromosomal integrons (SCI) that have driven bacterial evolution for eons. The paradigm of SCI is the superintegron (SI), an extremely large integron located in the chromosome of Vibrio cholerae, the causative agent of Cholera disease. Despite its role in the adaptability of one of the deadliest pathogens in history, the SI is poorly characterized because it is only functional in its native genetic background, yet its presence interferes with, and precludes all studies performed in V. cholerae. I propose to solve this paradoxical situation by deleting the SI, an ambitious project not only for its size (126 Kb) but because it is highly stabilized by 17 toxin-antitoxin systems. To do so, I have developed SeqDelTA, a novel method that is already giving excellent preliminary results. I will then use V. cholerae∆SI to study fundamental aspects of SCIs, yet out of reach. I will elucidate the functions encoded in SI cassettes to understand the role and adaptive value of integrons in nature; I will also unravel the genesis of cassettes: how a gene is exapted from its genetic context to become a mobile module; and I will explore the circulation of antibiotic resistance cassettes among humans, animals, food, and the environment with a novel biosynthetic tool (the I3C). KryptonInt will open and explore the historically inaccessible field of study of SCIs.

Field of science

  • /natural sciences/biological sciences/genetics and heredity/chromosome
  • /natural sciences/biological sciences/microbiology/bacteriology
  • /humanities/history and archaeology/history
  • /medical and health sciences/basic medicine/pharmacology and pharmacy/drug resistance/multidrug resistance
  • /medical and health sciences/basic medicine/pharmacology and pharmacy/drug resistance/antibiotic resistance

Call for proposal

ERC-2018-STG
See other projects for this call

Funding Scheme

ERC-STG - Starting Grant

Host institution

UNIVERSIDAD COMPLUTENSE DE MADRID
Address
Avenida De Seneca 2
28040 Madrid
Spain
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 1 499 516

Beneficiaries (1)

UNIVERSIDAD COMPLUTENSE DE MADRID
Spain
EU contribution
€ 1 499 516
Address
Avenida De Seneca 2
28040 Madrid
Activity type
Higher or Secondary Education Establishments