title: Targeting the Osmotic Stress Response for Strain Improvement of an Industrial Producer of Secondary Metabolites.
abstract: The transition from primary to secondary metabolism in antibiotic-producing Streptomyces correlates with expression of genes involved in stress responses. Consequently, regulatory pathways that regulate specific stress responses are potential targets to manipulate to increase antibiotic titers. In this study, genes encoding key proteins involved in regulation of the osmotic stress response in Streptomyces avermitilis, the industrial producer of avermectins, are investigated as targets. Disruption of either osaBSa, encoding a response regulator protein, or osaCSa, encoding a multidomain regulator of the alternative sigma factor SigB, led to increased production of both oligomycin, by up to 200%, and avermectin, by up to 37%. The mutations also conditionally affected morphological development; under osmotic stress, the mutants were unable to erect an aerial mycelium. In addition, we demonstrate the delivery of DNA into a streptomycete using biolistics. The data reveal that information on stress regulatory responses can be integrated in rational strain improvement to improve yields of bioactive secondary metabolites.
authors.affiliation: Biotechnology Department, CBS Division, Metropolitan Autonomous University, Mexico.
authors.forename: Octavio
authors.initials: O
authors.lastname: Godinez
authors.affiliation: Institute of Life Science, College of Medicine, Swansea University, Swansea SA2 8PP, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Dyson
authors.affiliation: Institute of Life Science, College of Medicine, Swansea University, Swansea SA2 8PP, UK.
authors.forename: Ricardo
authors.initials: R
authors.lastname: del Sol
authors.affiliation: Biotechnology Department, CBS Division, Metropolitan Autonomous University, Mexico.
authors.forename: Javier
authors.initials: J
authors.lastname: Barrios-Gonzalez
authors.affiliation: Biotechnology Department, CBS Division, Metropolitan Autonomous University, Mexico.
authors.forename: Cesar
authors.initials: C
authors.lastname: Millan-Pacheco
authors.affiliation: Biotechnology Department, CBS Division, Metropolitan Autonomous University, Mexico.
authors.forename: Armando
authors.initials: A
authors.lastname: Mejia
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism*; D017353:Gene Deletion; D053263:Gene Regulatory Networks; D007559:Ivermectin / Q000031:analogs & derivatives / Q000378:metabolism; D060847:Metabolic Engineering; D009840:Oligomycins / Q000378:metabolism; D064587:Osmoregulation; D013302:Streptomyces / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology
chemical_list: D000900:Anti-Bacterial Agents; D009840:Oligomycins; D007559:Ivermectin; C019264:avermectin
keywords: Streptomyces; antibiotic production; avermectin; stress responses