In vitro biological evaluation of new antimycobacterial salicylanilide-tuftsin conjugates

Eur J Med Chem. 2017 Jun 16:133:152-173. doi: 10.1016/j.ejmech.2017.03.047.

Zsuzsa Baranyai ¹, Martin Krátký ², Rudolf Vosátka ³, Eleonóra Szabó ⁴, Zsuzsanna Senoner ⁵, Sándor Dávid ⁶, Jiřina Stolaříková ⁷, Jarmila Vinšová ⁸, Szilvia Bősze ⁹

Affiliations

1 MTA-ELTE Research Group of Peptide Chemistry, Pázmány Péter sétány 1/A, P.O. Box 32, 1518, H-1117 Budapest 112, Hungary. Electronic address: baranyaizsuzs@gmail.com.
2 Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Electronic address: martin.kratky@faf.cuni.cz.
3 Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Electronic address: vosatkar@faf.cuni.cz.
4 Laboratory of Bacteriology, Korányi National Institute for Tuberculosis and Respiratory Medicine, Pihenő út 1, Budapest H-1122, Hungary. Electronic address: nora.szabo@koranyi.hu.
5 Laboratory of Bacteriology, Korányi National Institute for Tuberculosis and Respiratory Medicine, Pihenő út 1, Budapest H-1122, Hungary. Electronic address: senonerzsuzsa@gmail.com.
6 MTA-ELTE Research Group of Peptide Chemistry, Pázmány Péter sétány 1/A, P.O. Box 32, 1518, H-1117 Budapest 112, Hungary; Laboratory of Bacteriology, Korányi National Institute for Tuberculosis and Respiratory Medicine, Pihenő út 1, Budapest H-1122, Hungary.
7 Laboratory for Mycobacterial Diagnostics and Tuberculosis, Regional Institute of Public Health in Ostrava, Partyzánské náměstí 7, 702 00 Ostrava, Czech Republic. Electronic address: jirina.stolarikova@zuova.cz.
8 Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Electronic address: jarmila.vinsova@faf.cuni.cz.
9 MTA-ELTE Research Group of Peptide Chemistry, Pázmány Péter sétány 1/A, P.O. Box 32, 1518, H-1117 Budapest 112, Hungary. Electronic address: bosze@elte.hu.

PMID: 28384546 DOI: 10.1016/j.ejmech.2017.03.047

Abstract

Tuberculosis is caused by Mycobacterium tuberculosis, an intracellular pathogen that can survive in host cells, mainly in macrophages. An increase of multidrug-resistant tuberculosis qualifies this infectious disease as a major public health problem worldwide. The cellular uptake of the antimycobacterial agents by infected host cells is limited. Our approach is to enhance the cellular uptake of the antituberculars by target cell-directed delivery using drug-peptide conjugates to achieve an increased intracellular efficacy. In this study, salicylanilide derivatives (2-hydroxy-N-phenylbenzamides) with remarkable antimycobacterial activity were conjugated to macrophage receptor specific tuftsin based peptide carriers through oxime bond directly or by insertion of a GFLG tetrapeptide spacer. We have found that the in vitro antimycobacterial activity of the salicylanilides against M. tuberculosis H₃₇Rv is preserved in the conjugates. While the free drug was ineffective on infected macrophage model, the conjugates were active against the intracellular bacteria. The fluorescently labelled peptide carriers that were modified with different fatty acid side chains showed outstanding cellular uptake rate to the macrophage model cells. The conjugation of the salicylanilides to tuftsin based carriers reduced or abolished the in vitro cytostatic activity of the free drugs with the exception of the palmitoylated conjugates. The conjugates degraded in the presence of rat liver lysosomal homogenate leading to the formation of an oxime bond-linked salicylanilide-amino acid fragment as the smallest active metabolite.

Keywords

Antimycobacterial activity; Cellular uptake; Fatty acid side chain; Intracellular bacteria; Salicylanilide; Tuftsin based carrier.

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