Tuberculosis (TB) is still a serious problem worldwide, particularly with the advent of drug-resistant strains. Using phenotypic screening, the authors have discovered quinoxaline compounds (especially Ty38c) that are active against extracellular and intracellular Mycobacterium tuberculosis, targeting DprE1, an enzyme involved in cell wall synthesis. The structural work reported in this paper will underpin further efforts to find other compounds that inhibit this target. There is no doubt that TB is a scourge of humankind, killing >1 million people each year. Current therapy is problematic owing to resistance issues and the long times over which drugs have to be taken. Current work has tended to move away from target-based screening to phenotypic screening. Using this approach, the authors have discovered the quinoxaline compound Ty38c as a TB drug candidate. Initial mutations were found in rv3405c, a transcriptional regulator that controls expression of rv3406, whose gene product inactivates Ty38c. Using an rv3406-deficient strain, the authors show that the actual target of Ty38c is DprE1, which is a known target for other TB inhibitors. Using a range of Ty38c analogues, the authors perform a series of structure-activity experiments, and using X-ray crystallography they reveal the molecular details of the Ty38c-DprE1 interactions. Taken together, the work represents a tour de force in TB drug discovery research and provides significant hope that new TB agents can be developed from such approaches.

Maxwell A: F1000Prime Recommendation of Evaluation [Neres J et al., ACS Chem Biol 2014]. In F1000Prime, 09 Jan 2015; DOI: 10.3410/f.725248139.793502885. F1000Prime.com/725248139#eval793502885 / Maxwell, Anthony; Neres, J; Hartkoorn, Rc; Chiarelli, Lr; Gadupudi, Ramakrishna; Pasca, Mr; Mori, G; Venturelli, Alberto; Savina, S; Makarov, V; Kolly, Gs; Molteni, E; Binda, C; Dhar, N; Ferrari, Stefania; Brodin, P; Delorme, V; Landry, V; de Jesus Lopes Ribeiro, Al; Farina, Davide Salvatore Francesco; Saxena, Puneet; Pojer, F; Carta, Antonello; Luciani, Rosaria; Porta, Andrea; Zanoni, G; De Rossi, E; Costi, Maria Paola; Riccardi, G.. - ELETTRONICO. - RECOMMENDATIONS 1 | ABSTRACT | COMMENTS expand all 09 Jan 2015 Exceptional:(2015), pp. 9-9. [10.3410/f.725248139.793502885]

Maxwell A: F1000Prime Recommendation of Evaluation [Neres J et al., ACS Chem Biol 2014]. In F1000Prime, 09 Jan 2015; DOI: 10.3410/f.725248139.793502885. F1000Prime.com/725248139#eval793502885

GADUPUDI, RAMAKRISHNA;VENTURELLI, Alberto;FERRARI, Stefania;FARINA, Davide Salvatore Francesco;SAXENA, PUNEET;CARTA, Antonello;LUCIANI, Rosaria;PORTA, Andrea;COSTI, Maria Paola;
2015

Abstract

Tuberculosis (TB) is still a serious problem worldwide, particularly with the advent of drug-resistant strains. Using phenotypic screening, the authors have discovered quinoxaline compounds (especially Ty38c) that are active against extracellular and intracellular Mycobacterium tuberculosis, targeting DprE1, an enzyme involved in cell wall synthesis. The structural work reported in this paper will underpin further efforts to find other compounds that inhibit this target. There is no doubt that TB is a scourge of humankind, killing >1 million people each year. Current therapy is problematic owing to resistance issues and the long times over which drugs have to be taken. Current work has tended to move away from target-based screening to phenotypic screening. Using this approach, the authors have discovered the quinoxaline compound Ty38c as a TB drug candidate. Initial mutations were found in rv3405c, a transcriptional regulator that controls expression of rv3406, whose gene product inactivates Ty38c. Using an rv3406-deficient strain, the authors show that the actual target of Ty38c is DprE1, which is a known target for other TB inhibitors. Using a range of Ty38c analogues, the authors perform a series of structure-activity experiments, and using X-ray crystallography they reveal the molecular details of the Ty38c-DprE1 interactions. Taken together, the work represents a tour de force in TB drug discovery research and provides significant hope that new TB agents can be developed from such approaches.
Maxwell, Anthony; Neres, J; Hartkoorn, Rc; Chiarelli, Lr; Gadupudi, Ramakrishna; Pasca, Mr; Mori, G; Venturelli, Alberto; Savina, S; Makarov, V; Kolly, Gs; Molteni, E; Binda, C; Dhar, N; Ferrari, Stefania; Brodin, P; Delorme, V; Landry, V; de Jesus Lopes Ribeiro, Al; Farina, Davide Salvatore Francesco; Saxena, Puneet; Pojer, F; Carta, Antonello; Luciani, Rosaria; Porta, Andrea; Zanoni, G; De Rossi, E; Costi, Maria Paola; Riccardi, G.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/1061627
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