Anti-Shigella activity and killing kinetics of compounds from MMV Pathogen and COVID Boxes: Identifying leads against Shigellosis
Abstract
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.
How strong is the evidence?
Evidence Hub reads this as a report, done in cell cultures (in vitro), not in people. Its evidence level is 5 of 5 (Very low · case / narrative / animal / in vitro / in silico). Case reports, narrative reviews, and animal, cell or computer-model studies give the weakest evidence for human health.
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