title: New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria.
abstract: Antibiotic resistance in medically relevant bacterial pathogens, coupled with a paucity of novel antimicrobial 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 virulent Yersinia pestis CO92 strain. Of these compounds, we identified 94 not classified as antibiotics as being effective at preventing Y. pestis-induced cytotoxicity. A total of 17 prioritized drugs, based on efficacy in in vitro screens, were chosen for further evaluation in a murine model of pneumonic plague to delineate if in vitro efficacy could be translated in vivo Three drugs, doxapram (DXP), amoxapine (AXPN), and trifluoperazine (TFP), increased animal survivability despite not exhibiting any direct bacteriostatic or bactericidal effect on Y. pestis and having no modulating effect on crucial Y. pestis virulence factors. These findings suggested that DXP, AXPN, and TFP may modulate host cell pathways necessary for disease pathogenesis. Finally, to further assess the broad applicability of drugs identified from in vitro screens, the therapeutic potential of TFP, the most efficacious drug in vivo, was evaluated in murine models of Salmonella enterica serovar Typhimurium and Clostridium difficile infections. In both models, TFP treatment resulted in increased survivability of infected animals. Taken together, these results demonstrate the broad applicability and potential use of nonantibiotic FDA-approved drugs to combat respiratory and gastrointestinal bacterial pathogens.
authors.affiliation: Institute for Translational Sciences, University of Texas Medical Branch (UTMB), Galveston, Texas, USA.
authors.forename: Jourdan A
authors.initials: JA
authors.lastname: Andersson
authors.affiliation: Department of Microbiology and Immunology, UTMB, Galveston, Texas, USA.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Fitts
authors.affiliation: Department of Microbiology and Immunology, UTMB, Galveston, Texas, USA.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Kirtley
authors.affiliation: Department of Microbiology and Immunology, UTMB, Galveston, Texas, USA.
authors.forename: Duraisamy
authors.initials: D
authors.lastname: Ponnusamy
authors.affiliation: Department of Internal Medicine, UTMB, Galveston, Texas, USA.
authors.forename: Alex G
authors.initials: AG
authors.lastname: Peniche
authors.affiliation: Department of Internal Medicine, UTMB, Galveston, Texas, USA Institute for Human Infections and Immunity, UTMB, Galveston, Texas, USA.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Dann
authors.affiliation: Department of Microbiology and Immunology, UTMB, Galveston, Texas, USA Institute for Human Infections and Immunity, UTMB, Galveston, Texas, USA Department of Pathology, UTMB, Galveston, Texas, USA WHO Collaborating Center for Vaccine Development, UTMB, Galveston, Texas, USA Center for Biodefense and Emerging Infectious Diseases, UTMB, Galveston, Texas, USA.
authors.forename: Vladimir L
authors.initials: VL
authors.lastname: Motin
authors.affiliation: Institute for Translational Sciences, University of Texas Medical Branch (UTMB), Galveston, Texas, USA.
authors.forename: Sadhana
authors.initials: S
authors.lastname: Chauhan
authors.affiliation: Department of Biology, Texas Southern University, Houston, Texas, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Rosenzweig
authors.affiliation: Department of Microbiology and Immunology, UTMB, Galveston, Texas, USA Institute for Human Infections and Immunity, UTMB, Galveston, Texas, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Sha
authors.affiliation: Institute for Translational Sciences, University of Texas Medical Branch (UTMB), Galveston, Texas, USA Department of Microbiology and Immunology, UTMB, Galveston, Texas, USA Institute for Human Infections and Immunity, UTMB, Galveston, Texas, USA WHO Collaborating Center for Vaccine Development, UTMB, Galveston, Texas, USA Center for Biodefense and Emerging Infectious Diseases, UTMB, Galveston, Texas, USA achopra@utmb.edu.
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Chopra
mesh_terms: D000657:Amoxapine / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D016360:Clostridioides difficile / Q000187:drug effects / Q000254:growth & development / Q000472:pathogenicity; D004195:Disease Models, Animal; D004315:Doxapram / Q000494:pharmacology; D004334:Drug Administration Schedule; D058492:Drug Repositioning; D004761:Enterocolitis, Pseudomembranous / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology / Q000401:mortality; D005260:Female; D057166:High-Throughput Screening Assays; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D010930:Plague / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology / Q000401:mortality; D055553:Prescription Drugs / Q000494:pharmacology; D012480:Salmonella Infections / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology / Q000401:mortality; D012486:Salmonella typhimurium / Q000187:drug effects / Q000254:growth & development / Q000472:pathogenicity; D054852:Small Molecule Libraries / Q000494:pharmacology; D016019:Survival Analysis; D014268:Trifluoperazine / Q000494:pharmacology*; D015010:Yersinia pestis / Q000187:drug effects / Q000254:growth & development / Q000472:pathogenicity
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D055553:Prescription Drugs; D054852:Small Molecule Libraries; D014268:Trifluoperazine; D004315:Doxapram; D000657:Amoxapine