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Design and syntheses of highly potent teixobactin analogues against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE) in vitro and in vivo

(2018) JOURNAL OF MEDICINAL CHEMISTRY. 61(5). p.2009-2017
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Abstract
The cyclic depsipeptide, teixobactin, kills a number of Grampositive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), and Mycobacterium tuberculosis without detectable resistance. To date, teixobactin is the only molecule in its class that has shown in vivo antibacterial efficacy. In this work, we designed and synthesized 10 new in vivo ready teixobactin analogues. These analogues showed highly potent antibacterial activities against Staphylococcus aureus, MRSA, and vancomycin-resistant enterococci (VRE) in vitro. One analogue, D-Arg(4)-Leu(10)-teixobactin, 2, was found to be noncytotoxic in vitro and in vivo. Moreover, topical instillation of peptide 2 in a mouse model of S. aureus keratitis decreased the bacterial bioburden (>99.0% reduction) and corneal edema significantly as compared to untreated mouse corneas. Collectively, our results have established the high therapeutic potential of a teixobactin analogue in attenuating bacterial infections and associated severities in vivo.
Keywords
ANTIMICROBIAL PEPTIDES, ENDURACIDIDINE, DISCOVERY

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Chicago
Parmar, Anish, Rajamani Lakshminarayanan, Abhishek Iyer, Venkatesh Mayandi, Eunice Tze Leng Goh, Daniel G Lloyd, Madhavi Latha S Chalasani, et al. 2018. “Design and Syntheses of Highly Potent Teixobactin Analogues Against Staphylococcus Aureus, Methicillin-resistant Staphylococcus Aureus (MRSA), Vancomycin-resistant Enterococci (VRE) in Vitro and in Vivo.” Journal of Medicinal Chemistry 61 (5): 2009–2017.
APA
Parmar, A., Lakshminarayanan, R., Iyer, A., Mayandi, V., Goh, E. T. L., Lloyd, D. G., Chalasani, M. L. S., et al. (2018). Design and syntheses of highly potent teixobactin analogues against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE) in vitro and in vivo. JOURNAL OF MEDICINAL CHEMISTRY, 61(5), 2009–2017.
Vancouver
1.
Parmar A, Lakshminarayanan R, Iyer A, Mayandi V, Goh ETL, Lloyd DG, et al. Design and syntheses of highly potent teixobactin analogues against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE) in vitro and in vivo. JOURNAL OF MEDICINAL CHEMISTRY. 2018;61(5):2009–17.
MLA
Parmar, Anish et al. “Design and Syntheses of Highly Potent Teixobactin Analogues Against Staphylococcus Aureus, Methicillin-resistant Staphylococcus Aureus (MRSA), Vancomycin-resistant Enterococci (VRE) in Vitro and in Vivo.” JOURNAL OF MEDICINAL CHEMISTRY 61.5 (2018): 2009–2017. Print.
@article{8546955,
  abstract     = {The cyclic depsipeptide, teixobactin, kills a number of Grampositive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), and Mycobacterium tuberculosis without detectable resistance. To date, teixobactin is the only molecule in its class that has shown in vivo antibacterial efficacy. In this work, we designed and synthesized 10 new in vivo ready teixobactin analogues. These analogues showed highly potent antibacterial activities against Staphylococcus aureus, MRSA, and vancomycin-resistant enterococci (VRE) in vitro. One analogue, D-Arg(4)-Leu(10)-teixobactin, 2, was found to be noncytotoxic in vitro and in vivo. Moreover, topical instillation of peptide 2 in a mouse model of S. aureus keratitis decreased the bacterial bioburden ({\textrangle}99.0\% reduction) and corneal edema significantly as compared to untreated mouse corneas. Collectively, our results have established the high therapeutic potential of a teixobactin analogue in attenuating bacterial infections and associated severities in vivo.},
  author       = {Parmar, Anish and Lakshminarayanan, Rajamani and Iyer, Abhishek and Mayandi, Venkatesh and Goh, Eunice Tze Leng and Lloyd, Daniel G and Chalasani, Madhavi Latha S and Verma, Navin Kumar and Prior, Stephen H and Beuerman, Roger W and Madder, Annemieke and Taylor, Edward J and Singh, Ishwar},
  issn         = {0022-2623},
  journal      = {JOURNAL OF MEDICINAL CHEMISTRY},
  language     = {eng},
  number       = {5},
  pages        = {2009--2017},
  title        = {Design and syntheses of highly potent teixobactin analogues against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE) in vitro and in vivo},
  url          = {http://dx.doi.org/10.1021/acs.jmedchem.7b01634},
  volume       = {61},
  year         = {2018},
}

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