Maximizing the therapeutic window of an antimicrobial drug by imparting mitochondrial sequestration in human cells
Mark P. Pereira, Shana O. Kelley
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.
Journal of the American Chemical Society
https://doi.org/10.1021/ja110246u
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toxicity INIS 100%
human cells INIS 100%
methotrexate INIS 100%
Methotrexate Pharmacology, Toxicology and Pharmaceutical Science 100%
Antiinfective Agent Pharmacology, Toxicology and Pharmaceutical Science 100%
Human Cell Biochemistry, Genetics and Molecular Biology 100%
Toxicity Pharmacology, Toxicology and Pharmaceutical Science 80%
drugs INIS 40%
Pereira, M. P., & Kelley, S. O. (2011). Maximizing the therapeutic window of an antimicrobial drug by imparting mitochondrial sequestration in human cells. Journal of the American Chemical Society, 133(10), 3260-3263. https://doi.org/10.1021/ja110246u
Pereira, Mark P. ; Kelley, Shana O. / Maximizing the therapeutic window of an antimicrobial drug by imparting mitochondrial sequestration in human cells. In: Journal of the American Chemical Society. 2011 ; Vol. 133, No. 10. pp. 3260-3263.
@article{1bbc3d97e6614159a40144ee14e4e0d8,
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 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.",
author = "Pereira, {Mark P.} and Kelley, {Shana O.}",
doi = "10.1021/ja110246u",
journal = "Journal of the American Chemical Society",
Pereira, MP & Kelley, SO 2011, 'Maximizing the therapeutic window of an antimicrobial drug by imparting mitochondrial sequestration in human cells', Journal of the American Chemical Society, vol. 133, no. 10, pp. 3260-3263. https://doi.org/10.1021/ja110246u
Maximizing the therapeutic window of an antimicrobial drug by imparting mitochondrial sequestration in human cells. / Pereira, Mark P.; Kelley, Shana O.
In: Journal of the American Chemical Society, Vol. 133, No. 10, 16.03.2011, p. 3260-3263.
T1 - Maximizing the therapeutic window of an antimicrobial drug by imparting mitochondrial sequestration in human cells
AU - Pereira, Mark P.
AU - Kelley, Shana O.
N2 - 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.
AB - 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.
U2 - 10.1021/ja110246u
DO - 10.1021/ja110246u
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
Pereira MP, Kelley SO. Maximizing the therapeutic window of an antimicrobial drug by imparting mitochondrial sequestration in human cells. Journal of the American Chemical Society. 2011 Mar 16;133(10):3260-3263. doi: 10.1021/ja110246u