Synthesis, antitubercular activity and mechanism of resistance of highly effective thiacetazone analogues

Geoffrey Coxon, Derek Craig, Rosa Milagros Corrales, Emilie Vialla, Laila Gannoun-Zaki, Laurent Kremer

Research output: Contribution to journalArticle

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Abstract

Defining the pharmacological target(s) of currently used drugs and developing new analogues with greater potency are both important aspects of the search for agents that are effective against drug-sensitive and drug-resistant Mycobacterium tuberculosis. Thiacetazone (TAC) is an anti-tubercular drug that was formerly used in conjunction with isoniazid, but removed from the antitubercular chemotherapeutic arsenal due to toxic side effects. However, several recent studies have linked the mechanisms of action of TAC to mycolic acid metabolism and TAC-derived analogues have shown increased
potency against M. tuberculosis. To obtain new insights into the molecular mechanisms of TAC resistance, we isolated and analyzed 10 mutants of M. tuberculosis that were highly resistant to TAC. One strain was found to be mutated in the methyltransferase MmaA4 at Gly101, consistent with its lack of oxygenated mycolic acids. All remaining strains harbored missense mutations in either HadA (at Cys61) or HadC (at Val85, Lys157 or Thr123), which are components of the bhydroxyacyl-ACP dehydratase complex that participates in the mycolic acid elongation step. Separately, a library of 31 new
TAC analogues was synthesized and evaluated against M. tuberculosis. Two of these compounds, 15 and 16, exhibited minimal inhibitory concentrations 10-fold lower than the parental molecule, and inhibited mycolic acid biosynthesis in a
dose-dependent manner. Moreover, overexpression of HadAB HadBC or HadABC in M. tuberculosis led to high level resistance to these compounds, demonstrating that their mode of action is similar to that of TAC. In summary, this study
uncovered new mutations associated with TAC resistance and also demonstrated that simple structural optimization of the TAC scaffold was possible and may lead to a new generation of TAC-derived drug candidates for the potential treatment of tuberculosis as mycolic acid inhibitors.
Original languageEnglish
Article numbere53162
Pages (from-to)1-13
Number of pages13
JournalPLOS One
Volume8
Issue number1
DOIs
Publication statusPublished - 3 Jan 2013

Fingerprint

Thioacetazone
Mycobacterium tuberculosis
resistance mechanisms
Mycolic Acids
drugs
synthesis
acids
mechanism of action
isoniazid
Pharmaceutical Preparations
missense mutation
methyltransferases
tuberculosis
Hydro-Lyases
Arsenals
adverse effects
biosynthesis
Multidrug-Resistant Tuberculosis
mutation
Structural optimization

Keywords

  • antitubercular activity
  • thiacetazone analogues
  • isoniazid

Cite this

Coxon, Geoffrey ; Craig, Derek ; Corrales, Rosa Milagros ; Vialla, Emilie ; Gannoun-Zaki, Laila ; Kremer, Laurent. / Synthesis, antitubercular activity and mechanism of resistance of highly effective thiacetazone analogues. In: PLOS One. 2013 ; Vol. 8, No. 1. pp. 1-13.
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Coxon, G, Craig, D, Corrales, RM, Vialla, E, Gannoun-Zaki, L & Kremer, L 2013, 'Synthesis, antitubercular activity and mechanism of resistance of highly effective thiacetazone analogues', PLOS One, vol. 8, no. 1, e53162, pp. 1-13. https://doi.org/10.1371/journal.pone.0053162

Synthesis, antitubercular activity and mechanism of resistance of highly effective thiacetazone analogues. / Coxon, Geoffrey; Craig, Derek; Corrales, Rosa Milagros; Vialla, Emilie; Gannoun-Zaki, Laila; Kremer, Laurent.

In: PLOS One, Vol. 8, No. 1, e53162, 03.01.2013, p. 1-13.

Research output: Contribution to journalArticle

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T1 - Synthesis, antitubercular activity and mechanism of resistance of highly effective thiacetazone analogues

AU - Coxon, Geoffrey

AU - Craig, Derek

AU - Corrales, Rosa Milagros

AU - Vialla, Emilie

AU - Gannoun-Zaki, Laila

AU - Kremer, Laurent

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