Narrow-spectrum drug repurposing : targeting Gardnerella vaginalis biofilms associated with bacterial vaginosis

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Aim: Bacterial vaginosis (BV) is the most common vaginal disorder in women of reproductive age. Current therapies are limited by poor activity against biofilms and high recurrence rates (>50%), demonstrating that new antimicrobials are required. Drug repurposing is an attractive approach for the discovery of new antimicrobials, so we aimed to screen repurposed libraries for activity against the key BV pathobiont Gardnerella vaginalis. Methods and results: Two drug libraries from Medicines for Malaria Venture comprising 640 compounds were screened against G. vaginalis and various Lactobacilli species. Initial screening identified 16 G. vaginalis-selective compounds, of which 10 showed ≥90% inhibition of planktonic growth while sparing Lactobacillus crispatus. Subsequent assays revealed that three candidates displayed activity against pre-formed G. vaginalis biofilms; MMV1634360 (an antiproliferative compound with reported anticancer and antifungal activity), MMV1582487 (originally developed as an Escherichia coli aminopeptidase N inhibitor), and MMV1582497 (a thymidylate kinase inhibitor developed for Mycobacterium tuberculosis). All three produced >2-log reduction in viable cell counts at 10 µM (P < 0.05 for all compounds). Further cytotoxicity testing in VK2/E6E7 vaginal epithelial cells excluded MMV1634360 and MMV1582497 due to off-target effects, leaving MMV1582487 as a leading candidate. MMV1582487 demonstrated further activity against a high biofilm-forming G. vaginalis clinical isolate with >4log10 CFU/ml reduction in viable cell counts at 10 µM (P < 0.001), and synergy with existing antibiotic therapy. Conclusions: We demonstrate that MMV1582487 is a selective, non-cytotoxic, anti-biofilm candidate against G. vaginalis, supporting its potential as a novel therapeutic option for BV.

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