Polyketide synthase 12 is an in vivo essential source of novel mycolyl lipids in Mycobacterium tuberculosis

Mycobacterium tuberculosis (Mtb) is a major global pathogen that infects and transmits only among humans, yet nearly all in vivo virulence research is conducted in non-human hosts, a central challenge for tuberculosis research.

To overcome this, researchers leveraged a dataset of more than 50,000 sequenced isolates to identify Mtb genes that are functionally preserved during natural human infection, disease causation, and transmission. This whole-genome ranking identified polyketide synthase 12 (pks12) as an exceptionally in vivo essential gene in human tuberculosis, which the authors validated in zebrafish and mouse models.

Although Pks12 produces a mycoketide lipid in only trace amounts, deleting pks12 severely altered the host-facing surface and arabinoglycan architecture of Mtb. This amplified effect was explained by the discovery of mannosyl-beta-1-phosphomycoketide monomycolate (MPMMM), which is synthesized from the known Pks12 product at higher abundance by antigen 85 mycolyltransferases.

Overall, the study used a new host-facing genomic-metabolomic-phenotypic approach to discover the functions of an in vivo essential Mtb gene that controls the physical structure of the Mtb-host interface.