Activity of 2-(quinolin-4-yloxy)acetamides in Mycobacterium tuberculosis clinical isolates and identification of their molecular target by whole-genome sequencing

• Published in: International journal of antimicrobial agents 2018-03, Vol.51 (3), p.378-384
• Main Authors: Subtil, Fernanda Teixeira, Villela, Anne Drumond, Abbadi, Bruno Lopes, Rodrigues-Junior, Valnês S., Bizarro, Cristiano Valim, Timmers, Luis Fernando Saraiva Macedo, de Souza, Osmar Norberto, Pissinate, Kenia, Machado, Pablo, López-Gavín, Alexandre, Tudó, Griselda, González-Martín, Julian, Basso, Luiz Augusto, Santos, Diógenes Santiago
• Format: Article
• Language: English
• Subjects: Clinical isolates; Drug discovery; Quinoloxyacetamides; Target identification; Tuberculosis
• ISSN: 0924-8579; 1872-7913
• DOI: 10.1016/j.ijantimicag.2017.08.023

•Quinoloxyacetamides are active against clinical isolates resistant to main tuberculosis (TB) drugs.•Quinoloxyacetamides do not target DNA gyrase from Mycobacterium tuberculosis.•Whole-genome sequencing (WGS) data from spontaneous mutants reveal a single mutation in qcrB gene.•Quinoloxyacetamides target the subunit B of the cytochrome bc1 complex.•The 313 amino acid residue of QcrB protein plays key role in drug interaction. The 2-(quinolin-4-yloxy)acetamides (QOAs) have been reported to be promising molecules for tuberculosis treatment. Recent studies demonstrated their potent antimycobacterial activity, biological stability and synergism with rifampicin. The identification of the molecular target is an essential step towards the development of a novel drug candidate. Here, we report the target identification of the QOAs. We found that these compounds are active against Mycobacterium tuberculosis clinical isolates resistant to isoniazid, rifampicin, ethambutol, streptomycin and ethionamide. The initial evidence that DNA gyrase might be the target of QOAs, based on high minimum inhibitory concentration (MIC) values against ofloxacin-resistant clinical isolates and structural similarities with fluoroquinolones, was discarded by experiments performed with M. tuberculosis GyrA point mutant, DNA gyrase supercoiling inhibition assay and overexpression of DNA gyrase. We selected spontaneous mutants for our lead compound 21 and observed that these strains were also resistant to all QOA derivatives. The genomes of the spontaneous mutants were sequenced, and the results revealed a single mutation in qcrB gene (T313A), which indicates that the QOAs target the cytochrome bc1 complex. The protein-compound interaction was further investigated by molecular docking. These findings reinforce the relevance of these compounds as promising candidates for the treatment of multidrug-resistant tuberculosis.