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Rationally Improving Doramectin Production in Industrial Streptomyces avermitilis Strains

Avermectins (AVMs), a family of 16-membered macrocyclic macrolides produced by Streptomyces avermitilis, have been the most successful microbial natural antiparasitic agents in recent decades. Doramectin, an AVM derivative produced by S. avermitilis bkd(−) mutants through cyclohexanecarboxylic acid...

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Autores principales: Dang, Fujun, Xu, Qingyu, Qin, Zhongjun, Xia, Haiyang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10295569/
https://www.ncbi.nlm.nih.gov/pubmed/37370670
http://dx.doi.org/10.3390/bioengineering10060739
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author Dang, Fujun
Xu, Qingyu
Qin, Zhongjun
Xia, Haiyang
author_facet Dang, Fujun
Xu, Qingyu
Qin, Zhongjun
Xia, Haiyang
author_sort Dang, Fujun
collection PubMed
description Avermectins (AVMs), a family of 16-membered macrocyclic macrolides produced by Streptomyces avermitilis, have been the most successful microbial natural antiparasitic agents in recent decades. Doramectin, an AVM derivative produced by S. avermitilis bkd(−) mutants through cyclohexanecarboxylic acid (CHC) feeding, was commercialized as a veterinary antiparasitic drug by Pfizer Inc. Our previous results show that the production of avermectin and actinorhodin was affected by several other polyketide biosynthetic gene clusters in S. avermitilis and Streptomyces coelicolor, respectively. Thus, here, we propose a rational strategy to improve doramectin production via the termination of competing polyketide biosynthetic pathways combined with the overexpression of CoA ligase, providing precursors for polyketide biosynthesis. fadD17, an annotated putative cyclohex-1-ene-1-carboxylate:CoA ligase-encoding gene, was proven to be involved in the biosynthesis of doramectin. By sequentially removing three PKS (polyketide synthase) gene clusters and overexpressing FadD17 in the strain DM203, the resulting strain DM223 produced approximately 723 mg/L of doramectin in flasks, which was approximately 260% that of the original strain DM203 (approximately 280 mg/L). To summarize, our work demonstrates a novel viable approach to engineer doramectin overproducers, which might contribute to the reduction in the cost of this valuable compound in the future.
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spelling pubmed-102955692023-06-28 Rationally Improving Doramectin Production in Industrial Streptomyces avermitilis Strains Dang, Fujun Xu, Qingyu Qin, Zhongjun Xia, Haiyang Bioengineering (Basel) Communication Avermectins (AVMs), a family of 16-membered macrocyclic macrolides produced by Streptomyces avermitilis, have been the most successful microbial natural antiparasitic agents in recent decades. Doramectin, an AVM derivative produced by S. avermitilis bkd(−) mutants through cyclohexanecarboxylic acid (CHC) feeding, was commercialized as a veterinary antiparasitic drug by Pfizer Inc. Our previous results show that the production of avermectin and actinorhodin was affected by several other polyketide biosynthetic gene clusters in S. avermitilis and Streptomyces coelicolor, respectively. Thus, here, we propose a rational strategy to improve doramectin production via the termination of competing polyketide biosynthetic pathways combined with the overexpression of CoA ligase, providing precursors for polyketide biosynthesis. fadD17, an annotated putative cyclohex-1-ene-1-carboxylate:CoA ligase-encoding gene, was proven to be involved in the biosynthesis of doramectin. By sequentially removing three PKS (polyketide synthase) gene clusters and overexpressing FadD17 in the strain DM203, the resulting strain DM223 produced approximately 723 mg/L of doramectin in flasks, which was approximately 260% that of the original strain DM203 (approximately 280 mg/L). To summarize, our work demonstrates a novel viable approach to engineer doramectin overproducers, which might contribute to the reduction in the cost of this valuable compound in the future. MDPI 2023-06-20 /pmc/articles/PMC10295569/ /pubmed/37370670 http://dx.doi.org/10.3390/bioengineering10060739 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Communication
Dang, Fujun
Xu, Qingyu
Qin, Zhongjun
Xia, Haiyang
Rationally Improving Doramectin Production in Industrial Streptomyces avermitilis Strains
title Rationally Improving Doramectin Production in Industrial Streptomyces avermitilis Strains
title_full Rationally Improving Doramectin Production in Industrial Streptomyces avermitilis Strains
title_fullStr Rationally Improving Doramectin Production in Industrial Streptomyces avermitilis Strains
title_full_unstemmed Rationally Improving Doramectin Production in Industrial Streptomyces avermitilis Strains
title_short Rationally Improving Doramectin Production in Industrial Streptomyces avermitilis Strains
title_sort rationally improving doramectin production in industrial streptomyces avermitilis strains
topic Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10295569/
https://www.ncbi.nlm.nih.gov/pubmed/37370670
http://dx.doi.org/10.3390/bioengineering10060739
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