Discovery of novel enhancers of isoniazid toxicity in Mycobacterium tuberculosis

The number of effective first-line antibiotics for the treatment of Mycobacterium tuberculosis infection is strongly limited to a few drugs. Due to emerging resistance against those drugs, second- and third-line antibiotics have been established in therapy with certain problems and also increasing m...

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Bibliographic Details
Main Authors: Lentz Fabian
Reiling Norbert
Martins Ana
Molnár József
Hilgeroth Andreas
Format: Article
Published: 2018
Series:MOLECULES 23 No. 4
doi:10.3390/molecules23040825

mtmt:3370143
Online Access:http://publicatio.bibl.u-szeged.hu/13367
Description
Summary:The number of effective first-line antibiotics for the treatment of Mycobacterium tuberculosis infection is strongly limited to a few drugs. Due to emerging resistance against those drugs, second- and third-line antibiotics have been established in therapy with certain problems and also increasing mycobacterial resistance. An alternative to such novel drugs or combined therapeutic regimes which may reduce resistance development is finding enhancers of mycobacterial drug effectiveness, especially enhancers that counteract causative resistance mechanisms. Such enhancers may reduce the extracellular drug efflux mediated by bacterial efflux pumps and thus enhance the intracellular drug toxicity. We developed novel 1,4-dihydropyridines (DHPs) as potential efflux pump inhibitors with some determined P-gp affinities. The influence on the antituberculotic drug toxicity has been investigated for three prominent antituberculotic drugs. Exclusive and selective toxicity enhancing effects have been detected for isoniazid (INH) which could be related to certain substituent effects of the 1,4-DHPs. So, structure-dependent activities have been found. Thus, promising enhancers could be identified and a suggested efflux pump inhibition is discussed.
Physical Description:Terjedelem: 9 p.-Azonosító: 825
ISSN:1420-3049