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Mycobacterial Polyketide Virulence Factors: Biosynthesis and Inhibition

Phenolic glycolipids (PGLs) are virulence factors produced by Mycobacterium tuberculosis, Mycobacterium leprae, and other important mycobacterial pathogens. PGLs play key roles in pathogenicity and host‐pathogen interaction by virtue of their immunomodulatory properties or, in the case of leprosy, their ability to cause peripheral nerve degeneration. Moreover, PGL production has been suggested as a trait predisposing M. tuberculosis strains of the W‐Beijing family to their characteristic epidemic spread and increased likelihood of developing drug resistance. Bioinformatic, genetic, and biochemical approaches were used to illuminate the mechanism for assembly of p‐hydroxyphenylalkanoate intermediates of PGL biosynthesis. Our studies demonstrate a functional cooperation between a coenzyme A‐independent didomain initiation module (FadD22) and a 6‐domain reducing iterative type I polyketide synthase (Pks15/1) for production of p hydroxyphenylalkanoate intermediates in in vitro and in vivo FadD22‐Pks15/1 reconstituted systems. Our results suggest that Pks15/1 has a relaxed control of catalytic cycle iterations, a mechanistic property that explains the origin of a characteristic alkyl chain length variability seen in PGLs. Finally, these new insights into the mechanism of PGL assembly were used to rationally develop the first inhibitor of PGL biosynthesis.