Engineering the biosynthesis of the polyketide-nonribosomal peptide collismycin A for generation of analogs with neuroprotective activity

Ignacio Garcia; Natalia M. Vior; Javier González-Sabín; Alfredo F. Braña; Jürgen Rohr; Francisco Moris; Carmen Méndez; José A. Salas

doi:10.1016/j.chembiol.2013.06.014

Engineering the biosynthesis of the polyketide-nonribosomal peptide collismycin A for generation of analogs with neuroprotective activity

Ignacio Garcia
, Natalia M. Vior
, Javier González-Sabín
, Alfredo F. Braña
, Jürgen Rohr
, Francisco Moris
, Carmen Méndez
, José A. Salas

Research output: Contribution to journal › Article › peer-review

38 Scopus citations

Abstract

Collismycin A is a member of the 2,2′-bipyridyl family of natural products that shows cytotoxic activity. Structurally, it belongs to the hybrid polyketides-nonribosomal peptides. After the isolation and characterization of the collismycin A gene cluster, we have used the combination of two different approaches (insertional inactivation and biocatalysis) to increase structural diversity in this natural product class. Twelve collismycin analogs were generated with modifications in the second pyridine ring of collismycin A, thus potentially maintaining biologic activity. None of these analogs showed better cytotoxic activity than the parental collismycin. However, some analogs showed neuroprotective activity and one of them (collismycin H) showed better values for neuroprotection against oxidative stress in a zebrafish model than those of collismycin A. Interestingly, this analog also showed very poor cytotoxic activity, a feature very desirable for a neuroprotectant compound.

Original language	English
Pages (from-to)	1022-1032
Number of pages	11
Journal	Chemistry and Biology
Volume	20
Issue number	8
DOIs	https://doi.org/10.1016/j.chembiol.2013.06.014
State	Published - Aug 22 2013

Bibliographical note

Funding Information:
This research was supported by a grant (to J.A.S.) from the Spanish Ministry of Science and Innovation (BIO2009-07643) and the Plan Regional de Investigación del Principado de Asturias (PC10-05). N.V. was the recipient of a predoctoral fellowship of the Spanish Ministry of Science and Innovation (MICINN, FPI). We are very grateful to Carlos Olano for helpful discussions. We would like to thank Marcos Garcia Ocaña and ZFBiolabs (Madrid, Spain) for helping with the cytotoxicity and zebrafish assays, respectively.

Funding

This research was supported by a grant (to J.A.S.) from the Spanish Ministry of Science and Innovation (BIO2009-07643) and the Plan Regional de Investigación del Principado de Asturias (PC10-05). N.V. was the recipient of a predoctoral fellowship of the Spanish Ministry of Science and Innovation (MICINN, FPI). We are very grateful to Carlos Olano for helpful discussions. We would like to thank Marcos Garcia Ocaña and ZFBiolabs (Madrid, Spain) for helping with the cytotoxicity and zebrafish assays, respectively.

Funders	Funder number
Plan Regional de Investigación del Principado de Asturias	PC10-05
Family Process Institute Incorporated
Ministerio de Ciencia, Innovación y Universidades	BIO2009-07643

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

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10.1016/j.chembiol.2013.06.014

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title = "Engineering the biosynthesis of the polyketide-nonribosomal peptide collismycin A for generation of analogs with neuroprotective activity",

abstract = "Collismycin A is a member of the 2,2′-bipyridyl family of natural products that shows cytotoxic activity. Structurally, it belongs to the hybrid polyketides-nonribosomal peptides. After the isolation and characterization of the collismycin A gene cluster, we have used the combination of two different approaches (insertional inactivation and biocatalysis) to increase structural diversity in this natural product class. Twelve collismycin analogs were generated with modifications in the second pyridine ring of collismycin A, thus potentially maintaining biologic activity. None of these analogs showed better cytotoxic activity than the parental collismycin. However, some analogs showed neuroprotective activity and one of them (collismycin H) showed better values for neuroprotection against oxidative stress in a zebrafish model than those of collismycin A. Interestingly, this analog also showed very poor cytotoxic activity, a feature very desirable for a neuroprotectant compound.",

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note = "Funding Information: This research was supported by a grant (to J.A.S.) from the Spanish Ministry of Science and Innovation (BIO2009-07643) and the Plan Regional de Investigaci{\'o}n del Principado de Asturias (PC10-05). N.V. was the recipient of a predoctoral fellowship of the Spanish Ministry of Science and Innovation (MICINN, FPI). We are very grateful to Carlos Olano for helpful discussions. We would like to thank Marcos Garcia Oca{\~n}a and ZFBiolabs (Madrid, Spain) for helping with the cytotoxicity and zebrafish assays, respectively. ",

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AU - Méndez, Carmen

AU - Salas, José A.

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Engineering the biosynthesis of the polyketide-nonribosomal peptide collismycin A for generation of analogs with neuroprotective activity

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

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