The changes in mycolic acid structures caused byhadCmutation have a dramatic effect on the virulence ofMycobacterium tuberculosis

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Understanding the molecular strategies used byMycobacterium tuberculosisto invade and persist within the host is of paramount importance to tackle the tuberculosis pandemic. Comparative genomic surveys have revealed thathadC, encoding a subunit of the HadBC dehydratase, is mutated in the avirulentM. tuberculosisH37Ra strain. We show here that mutation or deletion ofhadCaffects the biosynthesis of oxygenated mycolic acids, substantially reducing their production level. Additionally, it causes the loss of atypical extra-long mycolic acids, demonstrating the involvement of HadBC in the late elongation steps of mycolic acid biosynthesis. These events have an impact on the morphotype, cording capacity and biofilm growth of the bacilli as well as on their sensitivity to agents such as rifampicin. Furthermore, deletion ofhadCleads to a dramatic loss of virulence: an almost 4-log drop of the bacterial load in the lungs and spleens of infected immunodeficient mice. Both its unique function and importance forM. tuberculosisvirulence make HadBC an attractive therapeutic target for tuberculosis drug development.

The present study shows that HadBC enzyme from Mycobacterium tuberculosis is a unique dehydratase implicated in late elongation steps within the biosynthesis pathway of the oxygenated and extra-long mycolic acids, key lipids of the envelope. HadBC function plays a role in the morphotype, cording property, biofilm formation and sensitivity to certain antibiotics, and is also required for the full virulence of the tubercle bacillus. Thus, HadBC constitutes an attractive therapeutic target for tuberculosis drug development.

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