Mycobacterium tuberculosis is an intracellular pathogen and the uptake of the antimycobacterial compounds by host cells is limited. Novel antimycobacterials effective against intracellular bacteria are needed. New N-substituted derivatives of 4-aminosalicylic acid have been designed and evaluated. To achieve intracellular efficacy and selectivity, these compounds were conjugated to tuftsin peptides via oxime or amide bonds. These delivery peptides can target tuftsin- and neuropilin receptor-bearing cells, such as macrophages and various other cells of lung origin. We have demonstrated that the in vitro antimycobacterial activity of the 4-aminosalicylic derivatives against M. tuberculosis H37Rv was preserved in the peptide conjugates. The free drugs were ineffective on infected cells, but the conjugates were active against the intracellular bacteria and have the selectivity on various types of host cells. The intracellular distribution of the carrier peptides was assessed, and the peptides internalize and display mainly in the cytosol in a concentration-dependent manner. The penetration ability of the most promising carrier peptide OT5 was evaluated using Transwell-inserts and spheroids. The pentapeptide exhibited time- and concentration-dependent penetration across the non-contact monolayers. Also, the pentapeptide has a fair penetration rate towards the center of spheroids formed of EBC-1 cells.

Biomolecular Self assembly Research Group Institute of Materials and Environmental Chemistry Research Centre for Natural Sciences Magyar tudósok körútja 2 H 1117 Budapest Hungary

Department of Biological Physics Eötvös Loránd University Pázmány Péter sétány 1 A H 1117 Budapest Hungary; National Public Health Center Albert Flórián út 2 6 H 1097 Budapest Hungary

Department of Organic and Bioorganic Chemistry Faculty of Pharmacy Charles University Heyrovského 1203 500 05 Hradec Králové Czech Republic

ELKH ELTE Research Group of Peptide Chemistry Eötvös Loránd Research Network Eötvös Loránd University Pázmány Péter sétány 1 A H 1117 Budapest Hungary

ELKH ELTE Research Group of Peptide Chemistry Eötvös Loránd Research Network Eötvös Loránd University Pázmány Péter sétány 1 A H 1117 Budapest Hungary; Hevesy György PhD School of Chemistry Faculty of Science Institute of Chemistry Eötvös Loránd University Pázmány Péter sétány 1 A H 1117 Budapest Hungary; National Public Health Center Albert Flórián út 2 6 H 1097 Budapest Hungary

Faculty of Science Institute of Chemistry Eötvös Loránd University Pázmány Péter sétány 1 A H 1117 Budapest Hungary

Hevesy György PhD School of Chemistry Faculty of Science Institute of Chemistry Eötvös Loránd University Pázmány Péter sétány 1 A H 1117 Budapest Hungary; National Public Health Center Albert Flórián út 2 6 H 1097 Budapest Hungary

Laboratory of Interfaces and Nanostructures Eötvös Loránd University Pázmány Péter sétány 1 A H 1117 Budapest Hungary

Neuronal Network and Behavior Research Group Institute of Cognitive Neuroscience and Psychology Research Centre for Natural Sciences Magyar tudósok körútja 2 H 1117 Budapest Hungary

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