In Vitro Screening of a 1280 FDA-Approved Drugs Library against Multidrug-Resistant and Extensively Drug-Resistant Bacteria

Abstract

Alternative strategies against multidrug-resistant (MDR) bacterial infections are suggested to clinicians, such as drug repurposing, which uses rapidly available and marketed drugs. We gathered a collection of MDR bacteria from our hospital and performed a phenotypic high-throughput screening with a 1280 FDA-approved drug library. We used two Gram positive (Enterococcus faecium P5014 and Staphylococcus aureus P1943) and six Gram negative (Acinetobacter baumannii P1887, Klebsiella pneumoniae P9495, Pseudomonas aeruginosa P6540, Burkholderia multivorans P6539, Pandoraea nosoerga P8103, and Escherichia coli DSM105182 as the reference and control strain). The selected MDR strain panel carried resistance genes or displayed phenotypic resistance to last-line therapies such as carbapenems, vancomycin, or colistin. A total of 107 compounds from nine therapeutic classes inhibited >90% of the growth of the selected Gram negative and Gram positive bacteria at a drug concentration set at 10 µmol/L, and 7.5% were anticancer drugs. The common hit was the antiseptic chlorhexidine. The activity of niclosamide, carmofur, and auranofin was found against the selected methicillin-resistant S. aureus. Zidovudine was effective against colistin-resistant E. coli and carbapenem-resistant K. pneumoniae. Trifluridine, an antiviral, was effective against E. faecium. Deferoxamine mesylate inhibited the growth of XDR P. nosoerga. Drug repurposing by an in vitro screening of a drug library is a promising approach to identify effective drugs for specific bacteria.

Keywords: alternative strategy; antibiotic combination; drug repurposing; extensively-drug resistant bacteria; multidrug-resistant bacteria; old drugs.

Figure 1

Hits found after an in vitro screening of the 1280 drugs library for each bacterium according to their therapeutic class. On the left, we discarded the duplicates and found 107 hits for all the Gram positive and negative bacteria. Some drugs are classified in various therapeutic classes and can be either antibacterial, antifungal, or antiviral, so we first considered the antibacterial effect in our counting or the major known effect. This chart highlights that most molecules that are active in vitro against bacterial growth are anti-infectives. Only a few options among the 1280 molecules tested can inhibit the bacterial growth of P. nosoerga or P. aeruginosa. All the compounds per bacterium are detailed in Supplementary Table S1. MDR: multidrug-resistant; XDR: extensively drug-resistant.

Figure 2

Compounds with a common efficacy on the growth of Gram positive or Gram negative bacteria in this 1280 drugs screening at 10 µmol/L. These molecules must be further tested more carefully, particularly regarding CMI assays, pharmacokinetics and pharmacodynamics, and administration modes in relation to the type of infection, etc.

Figure 3

Mechanisms of action of in vitro effective drugs on Gram negative bacteria tested at 10 µM.