Discovery of Gemcitabine Derivatives as Potent Inhibitors Against Drug-Resistant Bacteria with Decreased Toxicity Profiles

The rapid emergence of antimicrobial resistance represents a major public health threaten, which necessitates the discovery of novel antibacterial agents. In this study, four gemcitabine derivatives were synthesized by introduction of aromatic substituents at the amine group. Then, the derivates were evaluated for in vitro antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) ATCC 33591 and methicillin-sensitive S. aureus (MSSA) ATCC 25923. All derivatives exhibited moderate or good antibacterial activity, among which GEM-3 displayed the most potent antibacterial activity with low minimum inhibitory concentration (MIC) values of 0.5 μg/mL against both MRSA ATCC 33591 and MSSA ATCC 25923. Furthermore, all derivatives showed low cytotoxicity toward human normal cells and tumor cells. Moreover, all derivatives exhibited low hemolytic rates. Besides, the molecular docking study implied that these derivatives may work through targeting deoxyadenosine kinase. Taken together, with potent antibacterial activities and low toxicity profiles, gemcitabine derivatives may be promising lead compounds for antibacterial agents.