title: Maximizing the therapeutic window of an antimicrobial drug by imparting mitochondrial sequestration in human cells.
abstract: The number of antimicrobial agents available for use in humans is limited by the difficulty of discovering chemical agents with selective toxicity to bacterial targets. Numerous small molecule inhibitors have potential as antimicrobial agents, yet their use has been prevented by high levels of toxic cross-reactivity in human cells. For example, methotrexate (Mtx) is an effective antimetabolite that exerts its effects by inhibiting DHFR. It is a potent antibacterial when accumulated intracellularly, but toxicity in human cells limits clinical utility in infectious disease treatment. Here, we describe peptide conjugates of Mtx that are sequestered into the mitochondria of human cells (mt-Mtx). This alteration in localization of Mtx, which directs it away from its enzyme target, decreases its toxicity in human cells by a factor of 10(3). Mt-Mtx, however, maintains activity against a variety of pathogenic gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA). The results from this proof-of-principle study describe a novel methodology for augmenting the antibacterial efficacy of drugs amenable to peptide conjugation while simultaneously decreasing their toxicity to the host organism.
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Pereira
authors.forename: Shana O
authors.initials: SO
authors.lastname: Kelley
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000627:therapeutic use* / Q000633:toxicity; D001692:Biological Transport; D003141:Communicable Diseases / Q000188:drug therapy*; D004926:Escherichia coli / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008727:Methotrexate / Q000378:metabolism* / Q000627:therapeutic use* / Q000633:toxicity; D008928:Mitochondria / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D013296:Streptococcus pneumoniae / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D010455:Peptides; D008727:Methotrexate