Abstract:
:Ethionamide (ETH) is an important second-line antitubercular drug used for the treatment of patients infected with multidrug-resistant Mycobacterium tuberculosis. Although ETH is a structural analogue of isoniazid, only little cross-resistance to these two drugs is observed among clinical isolates. Both isoniazid and ETH are pro-drugs that need to be activated by mycobacterial enzymes to exert their antimicrobial activity. We have recently identified two M. tuberculosis genes, Rv3854c (ethA) and Rv3855 (ethR), involved in resistance to ETH. ethA encodes a protein that belongs to the Flavin-containing monooxygenase family catalysing the activation of ETH. We show here that ethR, which encodes a repressor belonging to the TetR/CamR family of transcriptional regulators, negatively regulates the expression of ethA. By the insertion of the ethA promoter region upstream of the lacZ reporter gene, overexpression of ethR in trans was found to cause a strong inhibition of ethA expression, independently of the presence of ETH in the culture media. Electrophoretic mobility shift assays indicated that EthR interacts directly with the ethA promoter region. This interaction was confirmed by DNA footprinting analysis, which, in addition, identified the EthR-binding region. Unlike other TetR/CamR members, which typically bind 15 bp operators, EthR recognises an unusually long 55 bp region suggesting multimerization of the repressor on its operator. Identification by primer-extension of the ethA transcriptional start site indicated that it is located within the EthR-binding region. Taken together, bacterial two-hybrid experiments and gel filtration assays suggested a dimerization of EthR in the absence of its operator. In contrast, surface plasmon resonance analyses showed that eight EthR molecules bind cooperatively to the 55 bp operator, which represents a novel repression mechanism for a TetR/CamR member.
journal_name
Mol Microbioljournal_title
Molecular microbiologyauthors
Engohang-Ndong J,Baillat D,Aumercier M,Bellefontaine F,Besra GS,Locht C,Baulard ARdoi
10.1046/j.1365-2958.2003.03809.xsubject
Has Abstractpub_date
2004-01-01 00:00:00pages
175-88issue
1eissn
0950-382Xissn
1365-2958pii
3809journal_volume
51pub_type
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