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Mechanisms of self-resistance in the platensimycin- and platencin-producing Streptomyces platensis MA7327 and MA7339 strains.

ABSTRACT: Platensimycin (PTM) and platencin (PTN) are potent inhibitors of bacterial fatty acid synthases and have emerged as promising antibacterial drug leads. We previously characterized the PTM and PTN biosynthetic machineries in the Streptomyces platensis producers. We now identify two mechanisms for PTM and PTN resistance in the S. platensis producers-the ptmP3 or ptnP3 gene within the PTM-PTN or PTN biosynthetic cluster and the fabF gene within the fatty acid synthase locus. PtmP3/PtnP3 and FabF confer PTM and PTN resistance by target replacement and target modification, respectively. PtmP3/PtnP3 also represents an unprecedented mechanism for fatty acid biosynthesis in which FabH and FabF are functionally replaced by a single condensing enzyme. These findings challenge the current paradigm for fatty acid biosynthesis and should be considered in future development of effective therapeutics targeting fatty acid synthase.

SUBMITTER: Peterson RM

PROVIDER: S-EPMC3966621 | BioStudies | 2014-01-01

REPOSITORIES: biostudies

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Expression of the platencin biosynthetic gene cluster in heterologous hosts yielding new platencin congeners.

Project description:Platensimycin (PTM) and platencin (PTN) are potent and selective inhibitors of bacterial and mammalian fatty acid synthases and have emerged as promising drug leads for both antibacterial and antidiabetic therapies. We have previously cloned and sequenced the PTM-PTN dual biosynthetic gene cluster from Streptomyces platensis MA7327 and the PTN biosynthetic gene cluster from S. platensis MA7339, the latter of which is composed of 31 genes encoding PTN biosynthesis, regulation, and resistance. We have also demonstrated that PTM or PTN production can be significantly improved upon inactivation of the pathway-specific regulator ptmR1 or ptnR1 in S. platensis MA7327 or MA7339, respectively. We now report engineered production of PTN and congeners in a heterologous Streptomyces host. Expression constructs containing the ptn biosynthetic gene cluster were engineered from SuperCos 1 library clones and introduced into five model Streptomyces hosts, and PTN production was achieved in Streptomyces lividans K4-114. Inactivation of ptnR1 was crucial for expression of the ptn biosynthetic gene cluster, thereby PTN production, in S. lividans K4-114. Six PTN congeners, five of which were new, were also isolated from the recombinant strain S. lividans SB12606, revealing new insights into PTN biosynthesis. Production of PTN in a model Streptomyces host provides new opportunities to apply combinatorial biosynthetic strategies to the PTN biosynthetic machinery for structural diversity.

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2017-01-01 | S-EPMC5421316 | BioStudies

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