title: Combatting bacterial infections by killing persister cells with mitomycin C.
abstract: Persister cells are a multi-drug tolerant subpopulation of bacteria that contribute to chronic and recalcitrant clinical infections such as cystic fibrosis and tuberculosis. Persisters are metabolically dormant, so they are highly tolerant to all traditional antibiotics which are mainly effective against actively growing cells. Here, we show that the FDA-approved anti-cancer drug mitomycin C (MMC) eradicates persister cells through a growth-independent mechanism. MMC is passively transported and bioreductively activated, leading to spontaneous cross-linking of DNA, which we verify in both active and dormant cells. We find MMC effectively eradicates cells grown in numerous different growth states (e.g. planktonic cultures and highly robust biofilm cultures) in both rich and minimal media. Additionally, MMC is a potent bactericide for a broad range of bacterial persisters, including commensal Escherichia coli K-12 as well as pathogenic species of E. coli, Staphylococcus aureus and Pseudomonas aeruginosa. We also demonstrate the efficacy of MMC in an animal model and a wound model, substantiating the clinical applicability of MMC against bacterial infections. Therefore, MMC is the first broad-spectrum compound capable of eliminating persister cells, meriting investigation as a new approach for the treatment of recalcitrant infections.
authors: Department of Chemical Engineering, Pennsylvania State University, University Park, PA, 16802-4400, USA.
authors: Brian W
authors: BW
authors: Kwan
authors: Department of Chemical Engineering, Pennsylvania State University, University Park, PA, 16802-4400, USA.
authors: Nityananda
authors: N
authors: Chowdhury
authors: Department of Chemical Engineering, Pennsylvania State University, University Park, PA, 16802-4400, USA.|Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, 16802-4400, USA.
authors: Thomas K
authors: TK
authors: Wood
mesh_terms: D000667:Ampicillin / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D018441:Biofilms / Q000254:growth & development; D017173:Caenorhabditis elegans / Q000187:drug effects; D002939:Ciprofloxacin / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D003550:Cystic Fibrosis / Q000382:microbiology; D004195:Disease Models, Animal; D024901:Drug Resistance, Multiple, Bacterial; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000382:microbiology; D048168:Escherichia coli K12 / Q000187:drug effects*; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology*; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D003432:Cross-Linking Reagents; D016685:Mitomycin; D002939:Ciprofloxacin; D000667:Ampicillin