Reactive dirty fragments: implications for tuberculosis drug discovery

被引:27
作者
Gopal, Pooja [1 ]
Dick, Thomas [1 ]
机构
[1] Natl Univ Singapore, Yong Loo Lin Sch Med, Natl Univ Hlth Syst, Antibacterial Drug Discovery Lab,Dept Microbiol, Singapore 117597, Singapore
基金
英国医学研究理事会;
关键词
PARA-AMINOSALICYLIC ACID; DIHYDROFOLATE-REDUCTASE; ANTITUBERCULOSIS DRUGS; PYRAZINOIC ACID; PYRAZINAMIDE; RESISTANCE; SYNTHASE; TARGET; GENE; CHEMOTHERAPY;
D O I
10.1016/j.mib.2014.06.015
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Reactive multi-target fragments, old synthetic antimycobacterials that are activated inside Mycobacterium tuberculosis bacilli and are smaller than the usual drug-like, single-target molecules, represent critical components of current tuberculosis chemotherapies. Recent studies showed that para-aminosalicylic acid is recognized as a substrate by dihydropteroate synthase and poisons the downstream folate pathway. Pyrazinamide, a key relapse-reducing drug, is metabolized by an amidase and the reaction product interferes with trans-translation, membrane potential and other targets. However, the mechanism of action of pyrazinamide remains ill-defined and needs to be understood to rationally approach treatment shortening. The success of small dirty drugs and prodrugs suggests that fragment-based whole cell screens should be re-introduced in our current antimycobacterial drug discovery efforts.
引用
收藏
页码:7 / 12
页数:6
相关论文
共 58 条
[1]   A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis [J].
Andries, K ;
Verhasselt, P ;
Guillemont, J ;
Göhlmann, HWH ;
Neefs, JM ;
Winkler, H ;
Van Gestel, J ;
Timmerman, P ;
Zhu, M ;
Lee, E ;
Williams, P ;
de Chaffoy, D ;
Huitric, E ;
Hoffner, S ;
Cambau, E ;
Truffot-Pernot, C ;
Lounis, N ;
Jarlier, V .
SCIENCE, 2005, 307 (5707) :223-227
[2]  
[Anonymous], GLOB TUB REP 2013
[3]   Mycobacterium tuberculosis dihydrofolate reductase is a target for isoniazid [J].
Argyrou, A ;
Vetting, MW ;
Aladegbami, B ;
Blanchard, JS .
NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2006, 13 (05) :408-413
[4]   Proteome-wide profiling of isoniazid targets in mycobacterium tuberculosis [J].
Argyrou, Argyrides ;
Jin, Lianji ;
Siconilfi-Baez, Linda ;
Angeletti, Ruth H. ;
Blanchard, John S. .
BIOCHEMISTRY, 2006, 45 (47) :13947-13953
[5]   INHA, A GENE ENCODING A TARGET FOR ISONIAZID AND ETHIONAMIDE IN MYCOBACTERIUM-TUBERCULOSIS [J].
BANERJEE, A ;
DUBNAU, E ;
QUEMARD, A ;
BALASUBRAMANIAN, V ;
UM, KS ;
WILSON, T ;
COLLINS, D ;
DELISLE, G ;
JACOBS, WR .
SCIENCE, 1994, 263 (5144) :227-230
[6]  
Barry CE, 2011, CURR TOP MED CHEM, V11, P1216
[7]   The spectrum of latent tuberculosis: rethinking the biology and intervention strategies [J].
Barry, Clifton E., III ;
Boshoff, Helena I. ;
Dartois, Veronique ;
Dick, Thomas ;
Ehrt, Sabine ;
Flynn, JoAnne ;
Schnappinger, Dirk ;
Wilkinson, Robert J. ;
Young, Douglas .
NATURE REVIEWS MICROBIOLOGY, 2009, 7 (12) :845-855
[8]   Isoniazid: An Update on the Multiple Mechanisms for a Singular Action [J].
Bernardes-Genisson, V. ;
Deraeve, C. ;
Chollet, A. ;
Bernadou, J. ;
Pratviel, G. .
CURRENT MEDICINAL CHEMISTRY, 2013, 20 (35) :4370-4385
[9]   Effects of pyrazinamide on fatty acid synthesis by whole mycobacterial cells and purified fatty acid synthase I [J].
Boshoff, HI ;
Mizrahi, V ;
Barry, CE .
JOURNAL OF BACTERIOLOGY, 2002, 184 (08) :2167-2172
[10]   Vane's discovery of the mechanism of action of aspirin changed our understanding of its clinical pharmacology [J].
Botting, Regina M. .
PHARMACOLOGICAL REPORTS, 2010, 62 (03) :518-525