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The fatty acid synthase type II (FAS-II) multienzyme system builds the main chain of mycolic acids (MAs), important lipid pathogenicity factors of  Mycobacterium tuberculosis  ( Mtb ). Due to their original structure, the identification of the (3  R )-hydroxyacyl-ACP dehydratases, HadAB and HadBC, of  Mtb  FAS-II complex required in-depth work. Here, we report the discovery of a third dehydratase protein, HadD  Mtb   (Rv0504c), whose gene is non-essential and sits upstream of  cmaA2  encoding a cyclopropane synthase dedicated to keto- and methoxy-MAs.  HadD   Mtb   deletion triggered a marked change in  Mtb  keto-MA content and size distribution, deeply impacting the production of full-size molecules. Furthermore, abnormal MAs, likely generated from 3-hydroxylated intermediates, accumulated. These data strongly suggest that HadD  Mtb   catalyzes the 3-hydroxyacyl dehydratation step of late FAS-II elongation cycles during keto-MA biosynthesis. Phenotyping of  Mtb hadD  deletion mutant revealed the influence of HadD  Mtb   on the planktonic growth, colony morphology and biofilm structuration, as well as on low temperature tolerance. Importantly, HadD  Mtb   has a strong impact on  Mtb  virulence in the mouse model of infection. The effects of the lack of HadD  Mtb   observed both  in vitro  and  in vivo  designate this protein as a bona fide target for the development of novel anti-TB intervention strategies.

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Discovery of a novel dehydratase of the fatty acid synthase type II critical for ketomycolic acid biosynthesis and virulence of Mycobacterium tuberculosis