Authors
Nichole Orr-Burks, Sarah R Hosking, Steven P Maher, Dennis E Kyle, Malina A Bakowski, Robert J Hogan, Eric R Lafontaine
Published in
PLoS pathogens. Volume 22. Issue 9. Pages e1014596. Sep 16, 2026. Epub Sep 16, 2026.
Abstract
Burkholderia pseudomallei (Bp) and Burkholderia mallei (Bm) are the etiological agents of the fatal diseases melioidosis and glanders, respectively. No licensed vaccine is available to protect against these facultative intracellular bacteria and treatment of infection is difficult, requiring intensive and prolonged antimicrobial therapy with low success rates due to intrinsic resistance of Bp and Bm to most antibiotics. This, combined with concerns regarding their adversarial use as biological warfare agents, emphasize an immediate need to identify novel and effective countermeasures for the organisms. Herein, we developed an in vitro high-content imaging, high-throughput screening platform and tested a Library of Pharmacologically Active Compounds (LOPAC) and the Repurposing, Focused Rescue, and Accelerated MEdchem (ReFRAME) library of small molecules for bioactive compounds protecting against bacterial intracellular replication, which is a key pathogenicity trait of Bp and Bm. We first analyzed confocal microscopy images of Burkholderia-infected monolayers of Vero E6 cells and established a reproducible endpoint readout that quantifies cytopathic effects and the formation of plaques during infection. Following this, we screened ~14,800 small molecules and identified 170 unique structures providing ≥ 75% inhibition of intracellular replication of Bp and Bm with EC50 values ranging from 1 pM to 9.99 µM. Of these hits, 23 were found to disrupt the intracellular replication of both organisms including 8 compounds targeting dihydrofolate reductase, 3 tetracycline-class antibiotics, an inhibitor of bacterial leucyl-tRNA synthetase (epetraborole), and 2 host-directed compounds targeting receptors on the surface of mammalian cells. Selected compounds were evaluated in vivo using a BALB/c mouse model of aerosol infection and we discovered that daily treatment with epetraborole (20 mg/kg) and the fluoroquinolone levofloxacin (5 mg/kg) completely protected mice against exposure to lethal doses of Bm and Bp, reducing bacterial burdens in the lungs and spleen to undetectable levels in all animals by day 14 post-challenge.
PMID:
42748203
Bibliographic data and abstract were imported from PubMed on 17 Sep 2026.
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