There is a pressing need to develop novel antimicrobials to circumvent the scourge of antimicrobial resistance.
The objective of this study is to identify non-antibiotic drugs with potent antimicrobial activity, within an
applicable clinical range. A library, containing 727 FDA approved drugs and small molecules, was screened
against ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter
baumannii, Pseudomonas aeruginosa, and Enterobacter cloacae). Drugs that showed antimicrobial activity in an
applicable clinical range were further tested in vitro and in vivo in an infected mouse model. The initial screening
identified 24 non-antibiotic drugs and clinical molecules active against Gram-positive pathogens including methicillin-
resistant S. aureus (MRSA) and vancomycin-resistant enterococcus (VRE) isolates. Two non-antibiotic drugs
showed activity against Gram-negative pathogens. Among the active non-antibiotic drugs, only ebselen (EB) and
5-fluoro-2'-deoxyuridine (FdUrd), showed bactericidal activity, in an applicable clinical range, against multi-drug-resistant Staphylococcus
isolates including MRSA, vancomycin-resistant S. aureus (VRSA), and vancomycin-intermediate S. aureus (VISA). The minimum
inhibitory concentration at which 90% of clinical isolates of S. aureus were inhibited (MIC90) was found to be 0.25 and 0.0039mg/L for
EB and FdUrd, respectively. Treatment with EB orally significantly increased mice survival in a lethal model of septicemic MRSAinfection
by (60%) compared to that of control. FdUrd oral and intraperitoneal treatment significantly enhanced mouse survival by 60%
and 100%, respectively. These data encourage screening and repurposing of non-antibiotic drugs and clinical molecules to treat
multidrug-resistant bacterial infections.