A multitarget approach to drug discovery inhibiting Mycobacterium tuberculosis PyrG and PanK.

Abstract:

:Mycobacterium tuberculosis, the etiological agent of the infectious disease tuberculosis, kills approximately 1.5 million people annually, while the spread of multidrug-resistant strains is of great global concern. Thus, continuous efforts to identify new antitubercular drugs as well as novel targets are crucial. Recently, two prodrugs activated by the monooxygenase EthA, 7947882 and 7904688, which target the CTP synthetase PyrG, were identified and characterized. In this work, microbiological, biochemical, and in silico methodologies were used to demonstrate that both prodrugs possess a second target, the pantothenate kinase PanK. This enzyme is involved in coenzyme A biosynthesis, an essential pathway for M. tuberculosis growth. Moreover, compound 11426026, the active metabolite of 7947882, was demonstrated to directly inhibit PanK, as well. In an independent screen of a compound library against PyrG, two additional inhibitors were also found to be active against PanK. In conclusion, these direct PyrG and PanK inhibitors can be considered as leads for multitarget antitubercular drugs and these two enzymes could be employed as a "double-tool" in order to find additional hit compounds.

journal_name

Sci Rep

journal_title

Scientific reports

authors

Chiarelli LR,Mori G,Orena BS,Esposito M,Lane T,de Jesus Lopes Ribeiro AL,Degiacomi G,Zemanová J,Szádocka S,Huszár S,Palčeková Z,Manfredi M,Gosetti F,Lelièvre J,Ballell L,Kazakova E,Makarov V,Marengo E,Mikusova K,Col

doi

10.1038/s41598-018-21614-4

subject

Has Abstract

pub_date

2018-02-16 00:00:00

pages

3187

issue

1

issn

2045-2322

pii

10.1038/s41598-018-21614-4

journal_volume

8

pub_type

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