Abstract
Atratumycin is a cyclodepsipeptide with activity against Mycobacteria tuberculosis isolated from deep-sea derived Streptomyces atratus SCSIO ZH16NS-80S. Analysis of the atratumycin biosynthetic gene cluster (atr) revealed that its biosynthesis is regulated by multiple factors, including two LuxR regulatory genes (atr1 and atr2), two ABC transporter genes (atr29 and atr30) and one Streptomyces antibiotic regulatory gene (atr32). In this work, three regulatory and two transporter genes were unambiguously determined to provide positive, negative and self-protective roles during biosynthesis of atratumycin through bioinformatic analyses, gene inactivations and trans-complementation studies. Notably, an unusual Streptomyces antibiotic regulatory protein Atr32 was characterized as a negative regulator; the function of Atr32 is distinct from previous studies. Five over-expression mutant strains were constructed by rational application of the regulatory and transporter genes; the resulting strains produced significantly improved titers of atratumycin that were ca. 1.7–2.3 fold greater than wild-type (WT) producer. Furthermore, the atratumycin gene cluster was successfully expressed in Streptomyces coelicolor M1154, thus paving the way for the transfer and recombination of large DNA fragments. Overall, this finding sets the stage for understanding the unique biosynthesis of pharmaceutically important atratumycin and lays the foundation for generating anti-tuberculosis lead compounds possessing novel structures.
Highlights
Marine-derived natural products represent a rich source of potential drug candidates
LuxR family proteins bind to DNA in a dimeric form and recognize hallmark sequences of given target gene’s regulatory region [9]
(CAE51066.1, Streptomyces natalensis), the results revealed that the HTH motifs of the LuxR family were highly conserved (Figure 1), which is mainly responsible for the protein multi-polarization and activation with gene promoters [10,11]
Summary
Marine-derived natural products represent a rich source of potential drug candidates. Over the past 50 years, more than 30,000 natural products have been discovered from the ocean and unique marine microbes have become a treasure trove of novel lead compounds [1,2]. Increases in TB co-infection rates with HIV and the proliferation of multi-drug resistant bacteria have severely limited the effectiveness of conventional antibiotics, making it urgent to identify new anti-TB drug candidates [3]. In our efforts to find anti-TB drugs from marine-derived Streptomyces, the microbe. Streptomyces atratus SCSIO ZH16 was found to generate a number of natural products with good activity against M. tuberculosis. Ilamycin and its derivatives produced by the S. atratus
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