Maximizing the therapeutic window of an antimicrobial drug by imparting mitochondrial sequestration in human cells

Mark P. Pereira, Shana O. Kelley

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

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 103. 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.

Original languageEnglish (US)
Pages (from-to)3260-3263
Number of pages4
JournalJournal of the American Chemical Society
Volume133
Issue number10
DOIs
StatePublished - Mar 16 2011
Externally publishedYes

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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