Antibacterial Properties Of The Diabetic Drug Metformin
Abstract
Antimicrobial resistance poses a serious global health threat, creating an urgent need for alternative therapeutic strategies. One promising approach is repurposing non-antibiotic drugs as antimicrobial agents or adjuncts to existing antimicrobial agents. Metformin, a widely used antidiabetic drug, has recently demonstrated antibacterial activity against various bacterial species. However, its mechanism of action and the bacterial response to metformin remain unclear and sometimes contradictory. This thesis investigates the antibacterial effects of metformin, its underlying molecular mechanisms, and how bacteria may adapt to its presence, especially relevant for diabetic patients with long-term exposure. In this thesis, metformin’s effects on bacterial growth, virulence factors, and efflux pump activity across multiple clinically relevant species were investigated. To gain mechanistic insight, transcriptomic profiling using RNA-seq was conducted, and TraDIS was used to identify essential genes under metformin stress. Additionally, combinations with mitochondrial inhibitors and different antibiotic classes were tested to assess synergistic or antagonistic interactions. In addition, an evolutionary experiment with continuous low-dose metformin exposure was performed to track phenotypic and genotypic changes. Metformin was found to exert strain-specific antibacterial effects, disrupting bacterial metabolism, redox balance, and proton motive force. It may also mimic natural…
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