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Cellular vacuolar ATPases (v-ATPase) play an important role in endosomal acidification, a critical step in influenza A virus (IAV) host cell infection. We investigated the antiviral activity of the v-ATPase inhibitor saliphenylhalamide (SaliPhe) and compared it with several older v-ATPase inhibitors concanamycin A, bafilomycin A1, (BafA) and archazolid B targeting the subunit c of the V0 sector.An in vitro assay was devised to quantify the anti-influenza effect of v-ATPase inhibitors by measuring green fluorescent protein fluorescence of a reporter IAV. These data were combined with cytotoxicity testing to calculate selectivity indices. Data were validated by testing v-ATPase inhibitors against wild-type IAV in vitro and in vivo in mice.In vitro SaliPhe blocked the proliferation of pandemic and multidrug resistant viruses at concentrations up to 51-fold below its cytotoxic concentrations. At essentially non-toxic concentrations, SaliPhe protected 62.5% of mice against a lethal challenge of a mouse-adapted influenza strain, while BafA at cytotoxic concentrations showed essentially no protection against infection with IAV (SaliPhe vs. BafA P < 0.001).Our results show that a distinct binding site of the proton translocation domain of cellular v-ATPase can be selectively targeted by a new generation v-ATPase inhibitor with reduced toxicity to treat influenza virus infections, including multi-resistant strains. Treatment strategies against influenza that target host cellular proteins are expected to be more resistant to virus mutations than drugs blocking viral proteins.