Format

Send to

Choose Destination
Molecules. 2018 Apr 4;23(4). pii: E825. doi: 10.3390/molecules23040825.

Discovery of Novel Enhancers of Isoniazid Toxicity in Mycobacterium tuberculosis.

Author information

1
Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, 06120 Halle, Germany. fabian.lentz@pharmazie.uni-halle.de.
2
Research Center of Borstel, Leibniz Lung Center, 23845 Borstel, Germany. nreiling@fz-borstel.de.
3
German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel, 23845 Borstel, Germany. nreiling@fz-borstel.de.
4
Department of Medical Microbiology, University of Szeged, 6720 Szeged, Hungary. anasfmartins@gmail.com.
5
Department of Medical Microbiology, University of Szeged, 6720 Szeged, Hungary. molnar.jozsef@med.u-szeged.hu.
6
Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, 06120 Halle, Germany. andreas.hilgeroth@pharmazie.uni-halle.de.

Abstract

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.

KEYWORDS:

antibacterial enhancing activity; derivatives; lead structure; structure-activity; synthesis

PMID:
29617279
PMCID:
PMC6017859
DOI:
10.3390/molecules23040825
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Multidisciplinary Digital Publishing Institute (MDPI) Icon for PubMed Central
Loading ...
Support Center