Lantibiotic mutants and chimeras of enhanced stability and...

C - Chemistry – Metallurgy – 12 – N

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C12N 15/31 (2006.01) A21D 2/26 (2006.01) A23L 3/3544 (2006.01) A23L 3/3571 (2006.01) A61K 38/16 (2006.01) A61L 2/16 (2006.01) C07K 14/315 (2006.01) C07K 14/32 (2006.01) C07K 19/00 (2006.01) C12N 15/62 (2006.01) C12P 21/02 (2006.01) A61K 38/00 (2006.01)

Patent

CA 2230933

Lantibiotics, such as nisin and subtilin, are peptides that are substantially modified post-translationally, such as by dehydration of serines and threonines and by formation of thioether crosslinkages. Lantibiotics are synthesized with a leader region that directs proper processing; this leader is specific both for the synthesizing organism and for the mature sequence. Chimeric lantibiotics were synthesized that contained the subtilin leader region and either a subtilin-nisin fusion or a nisin-subtilin fusion for the mature region. The nisin-subtilin chimera was efficiently processed into a functional lantibiotic, but the subtilin-nisin fusion produced a heterogeneous mixture of products, none of which had the expected properties of a correctly process polypeptide. This mixture contained a minor component with a specific activity exceeding that of nisin itself.

Les lantibiotiques, du type nisine et subtiline sont des peptides qui sont modifiés principalement après la phase de traduction, par exemple par déshydratation de sérines et de thréonines et par formation de réticulations de thioéthers. On synthétise ces lantibiotiques avec une région de tête qui dirige une maturation correcte, cette région de tête étant spécifique à la fois de l'organisme en cours de synthèse et de la séquence mature. On a synthétisé des lantibiotiques chimères qui contiennent la région de tête de la subtiline et soit une fusion subtiline-nisine soit une fusion nisine-subtiline pour la région mature. La chimère nisine-subtiline a été efficacement traitée pour obtenir un lantibiotique fonctionnel, mais la fusion subtiline-nisine a produit un mélange hétérogène de produits, dont aucun ne possédait les caractéristiques attendues d'un polypeptide amené correctement à maturité. Ce mélange contenant un composant mineur doté d'une activité spécifique dépassant celle de la nisine même.

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