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Molecules 2018, 23(4), 825;

Discovery of Novel Enhancers of Isoniazid Toxicity in Mycobacterium tuberculosis

Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, 06120 Halle, Germany
Research Center of Borstel, Leibniz Lung Center, 23845 Borstel, Germany
German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel, 23845 Borstel, Germany
Department of Medical Microbiology, University of Szeged, 6720 Szeged, Hungary
Author to whom correspondence should be addressed.
Received: 23 February 2018 / Revised: 26 March 2018 / Accepted: 1 April 2018 / Published: 4 April 2018
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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. View Full-Text
Keywords: antibacterial enhancing activity; synthesis; derivatives; structure-activity; lead structure antibacterial enhancing activity; synthesis; derivatives; structure-activity; lead structure

Scheme 1

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Lentz, F.; Reiling, N.; Martins, A.; Molnár, J.; Hilgeroth, A. Discovery of Novel Enhancers of Isoniazid Toxicity in Mycobacterium tuberculosis. Molecules 2018, 23, 825.

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