Discovery of repurposed drugs that disrupt intracellular replication of Burkholderia pseudomallei and Burkholderia mallei and protect against lethal aerosol infection
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…
Read the paper
Related studies
- Penicillins for Treatment of Pneumococcal Pneumonia: Does In Vitro Resistance Really Matter?
- Thiophenes—Naturally Occurring Plant Metabolites: Biological Activities and In Silico Evaluation of Their Potential as Cathepsin D Inhibitors
- Inhalable Mannosylated Rifampicin–Curcumin Co-Loaded Nanomicelles with Enhanced In Vitro Antimicrobial Efficacy for an Optimized Pulmonary Tuberculosis Therapy
- Development and validation of microbial bioassay for quantification of Levofloxacin in pharmaceutical preparations
- GC-MS Analysis and Biomedical Therapy of Oil from n-Hexane Fraction of Scutellaria edelbergii Rech. f.: In Vitro, In Vivo, and In Silico Approach
- Propranolol, chlorpromazine and diclofenac restore susceptibility of extensively drug-resistant (XDR)-Acinetobacter baumannii to fluoroquinolones
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.