Pyridomycin: Evaluating its antimycobacterial potential through the synthesis and testing of new analogues

Laqua, Katja; Richter, Adrian; Ramm, M.; Moellmann, Ute; Imming, Peter

doi:10.1055/s-0032-1321322

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“…The fact that many isoniazide‐resistant clinical isolates of Mycobacterium tuberculosis are sensitive to pyridomycin strongly highlights the efficacy of this drug, thus it has attracted considerable interest from chemists and biologists. For instance, much effort has been made to synthesize the pyridomycin scaffold to resemble the crystal structure of pyridomycin, thereby retaining the ability to bind to InhA and for combined therapy with other compounds …”

Section: Figurementioning

confidence: 99%

Functional Characterization of PyrG, an Unusual Nonribosomal Peptide Synthetase Module from the Pyridomycin Biosynthetic Pathway

Huang

Brock

et al. 2016

ChemBioChem

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Pyridomycin is an antimycobacterial cyclodepsipeptide assembled by a nonribosomal peptide synthetase/polyketide synthase hybrid system. Analysis of its cluster revealed a nonribosomal peptide synthetase (NRPS) module, PyrG, that contains two tandem adenylation domains and a PKS-type ketoreductase domain. In this study, we biochemically validated that the second A domain recognizes and activates α-keto-β-methylvaleric acid (2-KVC) as the native substrate; the first A domain was not functional but might play a structural role. The KR domain catalyzed the reduction of the 2-KVC tethered to the peptidyl carrier protein of PyrG in the presence of the MbtH family protein, PyrH. PyrG was demonstrated to recognize many amino acids. This substrate promiscuity provides the potential to generate pyridomycin analogues with various enolic acids moiety; this is important for binding InhA, a critical enzyme for cell-wall biosynthesis in Mycobacterium tuberculosis.

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Section: Figurementioning

confidence: 99%