Current research in pharmacology and drug discovery · 2026
Anti-Shigella activity and killing kinetics of compounds from MMV Pathogen and COVID Boxes: Identifying leads against Shigellosis.
СтатьяНазвание и аннотация: Перевод в очереди
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Tchokouaha Yamthe Lauve Rachel, Kengne Mediesse Francine, Melogmo Dongmo Yanick Kevin, Matchuenkam Gayap Sonia Raissa, Dize Darline, Tsouh Fokou Patrick Valere, Boyom Fabrice Fekam
Аннотация
BACKGROUND: Shigellosis is a leading diarrheal disease, posing critical public health challenges in low- and middle-income countries. Rising antibiotic resistance exacerbates treatment limitations.
METHODS: We screened 560 compounds from the MMV Pathogen and COVID Boxes for in vitro activity against Shigella flexneri, S. sonnei, and S. dysenteriae via resazurin-based microdilution. Cytotoxicity (RAW 264.7 cells) and killing kinetics against S. flexneri were assessed.
RESULTS: From the primary screen, 13 compounds (9 from the Pathogen Box, 4 from the COVID Box) showed potent anti-Shigella activity against S. flexneri (MIC ≤10 μM). Among these, seven non-antibiotic Pathogen Box compounds exhibited low-micromolar MICs (0.31-5 μM) and low cytotoxicity (CC50 > 100 μM). The known antibiotic levofloxacin (MMV687798) showed broad-spectrum activity (MIC 0.15-2.5 μM). MMV1804312 (salinomycin) was the most active COVID Box hit (MIC 1.25 μM). Time-kill assays revealed rapid, concentration-dependent bactericidal activity (≥3-log reduction within 4-6 h) for Pathogen Box compounds MMV675997 and MMV021660, while MMV000858 displayed bacteriostatic action.
CONCLUSION: This study identifies several novel, non-antibiotic leads from the MMV Pathogen Box with potent anti-Shigella activity and favorable cytotoxicity profiles, offering promising starting points for further development against drug-resistant shigellosis.
METHODS: We screened 560 compounds from the MMV Pathogen and COVID Boxes for in vitro activity against Shigella flexneri, S. sonnei, and S. dysenteriae via resazurin-based microdilution. Cytotoxicity (RAW 264.7 cells) and killing kinetics against S. flexneri were assessed.
RESULTS: From the primary screen, 13 compounds (9 from the Pathogen Box, 4 from the COVID Box) showed potent anti-Shigella activity against S. flexneri (MIC ≤10 μM). Among these, seven non-antibiotic Pathogen Box compounds exhibited low-micromolar MICs (0.31-5 μM) and low cytotoxicity (CC50 > 100 μM). The known antibiotic levofloxacin (MMV687798) showed broad-spectrum activity (MIC 0.15-2.5 μM). MMV1804312 (salinomycin) was the most active COVID Box hit (MIC 1.25 μM). Time-kill assays revealed rapid, concentration-dependent bactericidal activity (≥3-log reduction within 4-6 h) for Pathogen Box compounds MMV675997 and MMV021660, while MMV000858 displayed bacteriostatic action.
CONCLUSION: This study identifies several novel, non-antibiotic leads from the MMV Pathogen Box with potent anti-Shigella activity and favorable cytotoxicity profiles, offering promising starting points for further development against drug-resistant shigellosis.