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New role for FDA-approved drugs in combating antibiotic-resistant bacteria.
Antimicrob Agents Chemother. 2016 Apr 11;
Authors: Andersson JA, Fitts EC, Kirtley ML, Ponnusamy D, Peniche AG, Dann SM, Motin VL, Chauhan S, Rosenzweig JA, Sha J, Chopra AK
Abstract
Antibiotic resistance in medically relevant bacterial pathogens, coupled with a paucity of novel anti-microbial discoveries, represents a pressing global crisis. Traditional drug discovery is an inefficient and costly process; however, systematic screening of Food and Drug Administration (FDA)-approved therapeutics for other indications in humans offers a rapid alternative approach. In this study, we screened a library of 780 FDA-approved drugs to identify molecules that rendered RAW 264.7 murine macrophages resistant to cytotoxicity induced by the highly virulentYersinia pestisCO92 strain. Of these compounds, we identified 94, not classified as antibiotics, as being effective in preventingY. pestis-induced cytotoxicity. A total of 17 "down-selected" drugs, based on efficacy inin vitroscreens, were chosen for further evaluation in a murine model of pneumonic plague to delineate ifin vitroefficacy could be translatedin vivo Three drugs, doxapram (DXP), amoxapine (AXPN), and trifluoperazine (TFP), increased animal survivability despite not exhibiting any direct bacteriostatic or bactericidal effect onY. pestisand no modulating effect on crucialY. pestisvirulence factors. These findings suggested that DXP, AXPN and TFP could be modulating host-cell pathways necessary for disease pathogenesis. Finally, to further assess the broad applicability of drugs identified fromin vitroscreens, the therapeutic potential of TFP, the most efficacious drugin vivo, was evaluated in murine models ofSalmonella entericaserovar Typhimurium andClostridium difficileinfections. In both models, TFP treatment resulted in increased survivability of infected animals. Taken together, these results demonstrate the broad applicability and potential use non-antibiotic FDA-approved drugs to combat respiratory and gastro-intestinal bacterial pathogens.
PMID: 27067323 [PubMed - as supplied by publisher]