Polyketide synthase 12 is an in vivo essential source of novel mycolyl lipids in Mycobacterium tuberculosis
- 1Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA
Abstract
Mycobacterium tuberculosis (Mtb) is a major pathogen worldwide that infects and transmits only among humans, yet nearly all in vivo virulence research occurs in non-human hosts. To overcome this central challenge in tuberculosis research, we leveraged a dataset of more than 50,000 sequenced isolates to identify Mtb genes that that are functionally preserved during natural infection, disease causation, and transmission between humans. This whole-genome ranking identified polyketide synthase 12 (pks12 ) as an exceptionally in vivo essential gene in human tuberculosis, which we validated in zebrafish and mouse models. Though Pks12 produces a mycoketide lipid in only trace amounts, pks12 deletion severely altered the host-facing surface and arabinoglycan architecture of Mtb. This amplified effect was explained through the discovery of mannosyl-{beta}-1-phosphomycoketide monomycolate (MPMMM), which is synthesized from the known Pks12 product at higher abundance by antigen 85 mycolyltransferases. Thus, we used a new host-facing genomic-metabolomic-phenotypic approach to discover the functions of an in vivo essential Mtb gene, which controls the physical structure of the Mtb-host interface.
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BibTeX
@misc{babunovic2026polyketide,
title = {{Polyketide synthase 12 is an in vivo essential source of novel mycolyl lipids in Mycobacterium tuberculosis}},
author = {G. H. Babunovic and S. van der Niet and M. T. Gontijo and K. Abrahams and R. Sun and K. Bhatt and E. Meirav and C. Vilcheze and D. C. Young and L. Rosbach and I. Kanopaite and O. O. Adefisayo and K. M. Smith and A. M. Xet-Mull and V. G. Dellinger and E. Layre and C. M. Smith and W. R. Jacobs and A. Bhatt and G. S. Besra and D. M. Tobin and Q. Liu and N. van der Wel and D. B. Moody},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.25.754250},
url = {https://www.biorxiv.org/content/10.64898/2026.09.25.754250v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Polyketide synthase 12 is an in vivo essential source of novel mycolyl lipids in Mycobacterium tuberculosis
AU - G. H. Babunovic
AU - S. van der Niet
AU - M. T. Gontijo
AU - K. Abrahams
AU - R. Sun
AU - K. Bhatt
AU - E. Meirav
AU - C. Vilcheze
AU - D. C. Young
AU - L. Rosbach
AU - I. Kanopaite
AU - O. O. Adefisayo
AU - K. M. Smith
AU - A. M. Xet-Mull
AU - V. G. Dellinger
AU - E. Layre
AU - C. M. Smith
AU - W. R. Jacobs
AU - A. Bhatt
AU - G. S. Besra
AU - D. M. Tobin
AU - Q. Liu
AU - N. van der Wel
AU - D. B. Moody
PY - 2026
DA - 2026/09/25
PB - bioRxiv
DO - 10.64898/2026.09.25.754250
UR - https://www.biorxiv.org/content/10.64898/2026.09.25.754250v1
AB - Mycobacterium tuberculosis (Mtb) is a major pathogen worldwide that infects and transmits only among humans, yet nearly all in vivo virulence research occurs in non-human hosts. To overcome this central challenge in tuberculosis research, we leveraged a dataset of more than 50,000 sequenced isolates to identify Mtb genes that that are functionally preserved during natural infection, disease causation, and transmission between humans. This whole-genome ranking identified polyketide synthase 12 (pks12 ) as an exceptionally in vivo essential gene in human tuberculosis, which we validated in zebrafish and mouse models. Though Pks12 produces a mycoketide lipid in only trace amounts, pks12 deletion severely altered the host-facing surface and arabinoglycan architecture of Mtb. This amplified effect was explained through the discovery of mannosyl-{beta}-1-phosphomycoketide monomycolate (MPMMM), which is synthesized from the known Pks12 product at higher abundance by antigen 85 mycolyltransferases. Thus, we used a new host-facing genomic-metabolomic-phenotypic approach to discover the functions of an in vivo essential Mtb gene, which controls the physical structure of the Mtb-host interface.
ER -