BACKGROUND AND PURPOSE: New compounds and innovative therapeutic approaches are trying to prevent antimicrobial resistance, which has become a global health challenge. EXPERIMENTAL APPROACH: This study includes a series of twelve mono-, di- and trichlorinated 1-hydroxynaphthalene-2-carboxanilides designed as multitarget agents. All compounds were evaluated for their antistaphylococcal activity. Furthermore, MTT assay and chemoproteomic analysis of selected compounds were performed. Cytotoxicity in human cells was also tested. KEY RESULTS: N-(3,5-Dichlorophenyl)-1-hydroxynaphthalene-2-carboxamide (10) demonstrated activity comparable to or higher than clinically used drugs, with minimum inhibitory concentrations (MICs) of 0.37 μM. The compound was equally effective against clinical isolates of methicillin-resistant S. aureus. On the other hand, compound 10 showed 96 % inhibition of S. aureus respiration only at a concentration of 16× MIC. Chemoproteomic analysis revealed that the effect of agent 10 on staphylococci resulted in the downregulation of four proteins. This compound expressed no in vitro cytotoxicity up to a concentration of 30 μM. CONCLUSION: From the set of tested mono-, di- and trisubstituted derivatives, it is evident that the position of chlorine atoms is decisive for significant antistaphylococcal activity. Inhibition of energy metabolism does not appear to be one of the main mechanisms of action of compound 10; on the contrary, the antibacterial effect may likely be contributed by downregulation of proteins (especially ATP-dependent protease ATPase subunit HslU) involved in processes essential for bacterial survival and growth, such as protein, nucleotide/nucleic acid synthesis and efficient protein repair/degradation.

Department of Analytical Chemistry Faculty of Natural Sciences Comenius University Ilkovicova 6 842 15 Bratislava Slovakia

Department of Biochemistry Faculty of Medicine Masaryk University Kamenice 5 Brno 625 00 Czech Republic

Department of Chemical Drugs Faculty of Pharmacy Masaryk University Palackeho tr 1946 1 612 00 Brno Czech Republic

Department of Infectious Diseases and Microbiology Faculty of Veterinary Medicine University of Veterinary Sciences Brno Palackeho tr 1946 1 612 42 Brno Czech Republic

Department of Molecular Pharmacy Faculty of Pharmacy Masaryk University Palackeho tr 1946 1 612 00 Brno Czech Republic

Department of Pharmacology and Toxicology Faculty of Pharmacy Masaryk University Palackeho tr 1946 1 612 00 Brno Czech Republic

Institute of Chemistry University of Silesia Szkolna 9 40 006 Katowice Poland

Institute of Neuroimmunology Slovak Academy of Sciences Dubravska cesta 9 845 10 Bratislava Slovakia

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