New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria

Author:

Andersson Jourdan A.1,Fitts Eric C.2,Kirtley Michelle L.2,Ponnusamy Duraisamy2,Peniche Alex G.3,Dann Sara M.34,Motin Vladimir L.24567,Chauhan Sadhana1,Rosenzweig Jason A.8,Sha Jian24,Chopra Ashok K.12467

Affiliation:

1. Institute for Translational Sciences, University of Texas Medical Branch (UTMB), Galveston, Texas, USA

2. Department of Microbiology and Immunology, UTMB, Galveston, Texas, USA

3. Department of Internal Medicine, UTMB, Galveston, Texas, USA

4. Institute for Human Infections and Immunity, UTMB, Galveston, Texas, USA

5. Department of Pathology, UTMB, Galveston, Texas, USA

6. WHO Collaborating Center for Vaccine Development, UTMB, Galveston, Texas, USA

7. Center for Biodefense and Emerging Infectious Diseases, UTMB, Galveston, Texas, USA

8. Department of Biology, Texas Southern University, Houston, Texas, USA

Abstract

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.

Funder

HHS | National Institutes of Health

National Science Foundation

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

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