Antituberculosis drugs: Ten years of research

Janin, Yves L.

doi:10.1016/j.bmc.2007.01.030

Cited by 450 publications

(187 citation statements)

References 571 publications

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“…As the molecular weight can be accurately read from the spectra, ESI-MS has emerged as a powerful tool to monitor the formation of protein adducts of metallo-drugs and to identify the resulting metallic fragments attached to proteins (30). Prior to ESI-MS, the RecA intein and cisplatin were mixed at a 1:1 ratio and incubated for 48 h. Two major peaks for the platinated intein were observed, corresponding to binding of 1 mol of Pt(NH 3 ) 2 Cl ϩ or 1 mol of [Pt(NH 3 ) 2 ] 2ϩ to the protein (Fig. 3).…”

Section: In Vitro Inhibition Of the Mtu Reca Intein By Cisplatin-mentioning

confidence: 99%

“…Tuberculosis remains a leading cause of death worldwide (1,2), and the global emergence of multidrug-resistant Mycobacterium tuberculosis portends further challenges in TB 3 control (3). Considerable effort has been devoted to the development of new drugs in the treatment of tuberculosis, and the World Health Organization (WHO) launched a new Stop TB Strategy in 2006 to support these initiatives (4).…”

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Cisplatin Inhibits Protein Splicing, Suggesting Inteins as Therapeutic Targets in Mycobacteria

Zhang

Zheng

Callahan

et al. 2011

Journal of Biological Chemistry

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Mycobacterium tuberculosis harbors three protein splicing elements, called inteins, in critical genes and their protein products. Post-translational removal of the inteins occurs autocatalytically and is required for function of the respective M. tuberculosis proteins. Inteins are therefore potential targets for antimycobacterial agents. In this work, we report that the splicing activity of the intein present in the RecA recombinase of M. tuberculosis is potently inhibited by the anticancer drug cisplatin (cis-diamminedichloro-platinum(II)). This previously unrecognized activity of cisplatin was established using both an in vitro intein splicing assay, which yielded an IC 50 of ϳ2 M, and a genetic reporter for intein splicing in Escherichia coli. Testing of related platinum(II) complexes indicated that the inhibition activity is highly structure-dependent, with cisplatin exhibiting the best inhibitory effect. Finally, we report that cisplatin is toxic toward M. tuberculosis with a minimum inhibitory concentration of ϳ40 M, and in genetic experiments conducted with the related Mycobacterium bovis bacillus Calmette-Guérrin (BCG) strain, we show that cisplatin toxicity can be mitigated by intein overexpression. We propose that cisplatin inhibits intein activity by modifying at least one conserved cysteine residue that is required for splicing. Together these results identify a novel active site inhibitor of inteins and validate inteins as viable targets for small molecule inhibition in mycobacteria.Tuberculosis remains a leading cause of death worldwide (1, 2), and the global emergence of multidrug-resistant Mycobacterium tuberculosis portends further challenges in TB Several microbial pathogens, including M. tuberculosis, contain protein self-splicing elements called inteins, which interrupt critical genes and their protein products. These inteins are therefore potential novel targets for antibiotic development, particularly because no inteins are present in the human genome. In addition to M. tuberculosis, self-splicing inteins reside in critical proteins of Mycobacterium leprae, Coxiella burnetii, and Cryptococcus neoformans, the etiological agents of leprosy, Q fever, and cryptococcosis, respectively (6 -8). For these pathogens to survive, the inteins must catalyze a multistep reaction in which they are excised from the precursor protein and the two flanking sequences, called exteins, must be ligated to form a functional product protein (9 -11). Because inteins exert control, via splicing, over the function of pathogen-specific proteins, these self-splicing elements are attractive candidates for inhibition studies. The pursuit of intein inhibitors, whether as mechanistic probes or as an avenue for developing antibacterials, does face a unique challenge; unlike a conventional enzyme inhibitor, an effective antagonist of intein splicing must outcompete a substrate that is covalently tethered to the enzyme.M. tuberculosis has inteins in three distinct genes: in the dnaB helicase gene, in the recA recombinase gene,...

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Section: In Vitro Inhibition Of the Mtu Reca Intein By Cisplatin-mentioning

confidence: 99%

mentioning

confidence: 99%

Cisplatin Inhibits Protein Splicing, Suggesting Inteins as Therapeutic Targets in Mycobacteria

Zhang

Zheng

Callahan

et al. 2011

Journal of Biological Chemistry

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“…8 In the search of new compounds, isoniazid derivatives have been found to possess potential antitubercular activities. 9,10 Studies suggest that isoniazid, a prodrug which is converted into its active form by mycobacterial catalase-peroxidase, acts on the mycobacterial cell wall by preventing the FAS-II (fatty acid synthetase II) system from producing long chain fatty acid precursors for mycolic acid synthesis.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and antitubercular activity of isoniazid condensed with carbohydrate derivatives

et al. 2009

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Recebido em 23/9/08; aceito em 21/1/09; publicado na web em 14/7/09 A series of 13 compounds analogous of isoniazid condensed with carbohydrate was synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H 37 Rv using Alamar Blue susceptibility test and the activity expressed as the minimum inhibitory concentration (MIC 90 ) in µg/mL. Several compounds exhibited antitubercular activity (0.31-3.12 µg/mL) when compared with first line drugs such as isoniazid (INH) and rifampicin (RIP) and could be a good starting point to develop new compounds against tuberculosis.

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“…This increase of MDR-TB and emergence of XDR-TB provide the rationale to search for new antimycobacterial drugs. [2][3][4] Previously, we have reported the synthesis of 2-(substituted benzyl)sulfanyl derivatives of benzimidazole, 5) 5-methylbenzimidazole, 6) benzoxazole, 7) and benzothiazole 8) (XϭH, 4-NO 2 , 3-NO 2 , 2-NO 2 , 3,5-(NO 2 ) 2 , 2,4-(NO 2 ) 2 , 4-CN, 3-CN, only). General structure of these compounds is shown in Fig.…”

mentioning

confidence: 99%

Effect of Substitution on the Antimycobacterial Activity of 2-(Substituted benzyl)sulfanyl Benzimidazoles, Benzoxazoles, and Benzothiazoles-A Quantitative Structure-Activity Relationship Study

Pytela¹,

Klimešová

2011

CHEMICAL & PHARMACEUTICAL BULLETIN

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, and partially 4-NO 2 substituents possess the highest antimycobacterial activity. The effect of substitution was also described quantitatively with good correlation factor R of 0.79-0.88. The log MIC values depended with a negative slope on the Hammett substituent constants s s or molar refractions MR and, for the given set of substituents, were dominantly raised with increasing log P value and partially lowered with (log P) 2 or s s؋D D log P. The derivatives featuring high polarizability, low lipophilicity and electron-withdrawing subtituents showed the highest antimycobacterial activity. The dependence on the steric substituent constant v was not statistically significant and, therefore, the ortho effect was most probably not important.

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Antituberculosis drugs: Ten years of research

Cited by 450 publications

References 571 publications

Cisplatin Inhibits Protein Splicing, Suggesting Inteins as Therapeutic Targets in Mycobacteria

Cisplatin Inhibits Protein Splicing, Suggesting Inteins as Therapeutic Targets in Mycobacteria

Synthesis and antitubercular activity of isoniazid condensed with carbohydrate derivatives

Effect of Substitution on the Antimycobacterial Activity of 2-(Substituted benzyl)sulfanyl Benzimidazoles, Benzoxazoles, and Benzothiazoles-A Quantitative Structure-Activity Relationship Study

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