Combating multi-drug resistant pathogens with host-directed non-antibiotic therapeutics [PublishAheadOfPrint]

Earlier, we reported that 3 Food and Drug Administration-approved drugs, trifluoperazine (TFP, anti-psychotic), amoxapine (AXPN, anti-depressant), and doxapram (DXP, breathing stimulant), identified from an in vitro murine macrophage cytotoxicity screen, provided 40-60% protection to mice against pneumonic plague when administered at the time of infection for 1-3 days. In this study, the therapeutic potential of these drugs was further evaluated in mice when administered up to 48 h post-infection against pneumonic plague. While efficacy of TFP was somewhat diminished as treatment was delayed to 24 h, protection of mice with AXPN and DXP increased as treatment was progressively delayed to 24 h. At 48 h post infection, these drugs, when administered in combination with levofloxacin, provided significant, up to 100%, protection to animals against pneumonic or bubonic challenge. Likewise, when used in combination with vancomycin, all three drugs provided 80-100% protection from fatal oral Clostridium difficile infection in mice when administered 24 h post infection. Furthermore, AXPN provided 40-60% protection against respiratory infection with Klebsiella pneumoniae when administered at the time of infection or 24 h post infection. Using the same in vitro cytotoxicity assay, we identified additional 76/780 non-antibiotic drugs effective against K. pneumoniae. For Acinetobacter baumannii, 121 non-antibiotic drugs were identified to inhibit bacterial-induced cytotoxicity in murine macrophages. Of these 121 drugs, 13 inhibited macrophage cytotoxicity with two additional multiple-antibiotic resistant strains. Six of these drugs decreased intracellular survival of all three A. baumannii strains in macrophages. These results provided further evidence of the broad applicability and utilization of drug repurposing screening to identify new therapeutics to combat multi-drug resistant pathogens of public health concern.

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