Abstract
Ilamycins are cyclopeptides with novel structures that have been isolated from different Actinomycetes. They showed strong anti-tuberculosis activity and could serve as important anti-tuberculosis drug leads. The functions of the pre-tailoring and the post-tailoring genes in the biosynthesis of ilamycins have been elucidated, but the functions of the regulatory and transporter genes remain elusive. We reported herein the functions of four genes in ilamycin biosynthetic gene cluster (ila BGC) including two regulatory genes (ilaA and ilaB) and two transporter genes (ilaJ and ilaK) and the heterologous expression of ila BGC. The IlaA and IlaB were unambiguously shown to be negative and positive regulator of ilamycins biosynthesis, respectively. Consistent with these roles, inactivation of ilaA and ilaB (independent of each other) was shown to enhance and abolish the production of ilamycins, respectively. Total yields of ilamycins were enhanced 3.0-fold and 1.9-fold by inactivation of ilaA and overexpression of ilaB compared to those of in the Streptomyces atratus SCSIO ZH16, respectively. In addition, the ila BGC was successfully expressed in Streptomyces coelicolor M1152, which indicated that all biosynthetic elements for the construction of ilamycins were included in the PAC7A6. These results not only lay a foundation for further exploration of ilamycins, but also provide the genetic elements for synthetic biology.
Highlights
Marine derived Streptomyces have been identified as sources for novel natural products that are of great interest to drug discovery and development [1,2,3]
IlaK has six transmembrane domains similar with those in DrrB, MtrB, TnrB3, and Atr30. These results indicate that IlaJ and IlaK may work together, forming functional exporter units to mediate the secretion of ilamycins or the self-defense of S. atratus SCSIO ZH16 to ilamycins
We propose that IlaJ and IlaK play roles in the biosynthesis of ilamycins, such as the secretion of ilamycins or self-defense of S. atratus SCSIO ZH16 to ilamycins
Summary
Marine derived Streptomyces have been identified as sources for novel natural products that are of great interest to drug discovery and development [1,2,3]. Non-ribosomal peptides are an important class of natural products known for their structural diversity and bioactivity; many antitumor and anti-infective drugs are non-ribosomal peptides [4]. Known as rufomycins, are potent anti-TB cyclic heptapeptides containing three rare building blocks, l-3-nitrotyrosine, l-2-amino-4-hexenoic acid, and l-tryptophan, in which the indole nitrogen is alkylated with an isoprene or a modified isoprene unit. Eight more ilamycin analogs, ilamycins B1 (1), B2 (2), C1 (3), C2 (4), D (5), E1 (6), E2 , and F (Figure 1A), were isolated by our group from a marine
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