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The changes in mycolic acid structures caused by hadC mutation have a dramatic effect on the virulence of Mycobacterium tuberculosis
Author(s) -
Slama Nawel,
Jamet Stevie,
Frigui Wafa,
Pawlik Alexandre,
Bottai Daria,
Laval Françoise,
Constant Patricia,
Lemassu Anne,
Cam Kaymeuang,
Daffé Mamadou,
Brosch Roland,
Eynard Nathalie,
Quémard Annaïk
Publication year - 2016
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1111/mmi.13266
Subject(s) - mycolic acid , biology , mycobacterium tuberculosis , virulence , microbiology and biotechnology , tuberculosis , rifampicin , mycobacterium , virology , bacteria , genetics , antibiotics , gene , medicine , pathology
Summary Understanding the molecular strategies used by M ycobacterium tuberculosis to invade and persist within the host is of paramount importance to tackle the tuberculosis pandemic. Comparative genomic surveys have revealed that had C , encoding a subunit of the HadBC dehydratase, is mutated in the avirulent M . tuberculosis H37Ra strain. We show here that mutation or deletion of hadC affects 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 of had C leads 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 for M . tuberculosis virulence make HadBC an attractive therapeutic target for tuberculosis drug development.