AUTHOR=Martínez-Burgo Yolanda , Santos-Aberturas Javier , Rodríguez-García Antonio , Barreales Eva G. , Tormo José Rubén , Truman Andrew W. , Reyes Fernando , Aparicio Jesús F. , Liras Paloma 

TITLE=Activation of Secondary Metabolite Gene Clusters in Streptomyces clavuligerus by the PimM Regulator of Streptomyces natalensis

JOURNAL=Frontiers in Microbiology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2019.00580

DOI=10.3389/fmicb.2019.00580

ISSN=1664-302X

ABSTRACT=<p>Expression of non-native transcriptional activators may be a powerful general method to activate secondary metabolites biosynthetic pathways. PAS-LuxR regulators, whose archetype is PimM, activate the biosynthesis of polyene macrolide antifungals and other antibiotics, and have been shown to be functionally preserved across multiple <italic>Streptomyces</italic> strains. In this work we show that constitutive expression of <italic>pimM</italic> in <italic>Streptomyces clavuligerus</italic> ATCC 27064 significantly affected its transcriptome and modifies secondary metabolism. Almost all genes in three secondary metabolite clusters were overexpressed, including the clusters responsible for the biosynthesis of the clinically important clavulanic acid and cephamycin C. In comparison to a control strain, this resulted in 10- and 7-fold higher production levels of these metabolites, respectively. Metabolomic and bioactivity studies of <italic>S. clavuligerus::pimM</italic> also revealed deep metabolic changes. Antifungal activity absent in the control strain was detected in <italic>S. clavuligerus::pimM</italic>, and determined to be the result of a fivefold increase in the production of the tunicamycin complex.</p>