TY - JOUR
T1 - Design and Syntheses of Highly Potent Teixobactin Analogues against Staphylococcus aureus, Methicillin-Resistant Staphylococcus aureus (MRSA), and Vancomycin-Resistant Enterococci (VRE) in Vitro and in Vivo
AU - Parmar, Anish
AU - Lakshminarayanan, Rajamani
AU - Iyer, Abhishek
AU - Mayandi, Venkatesh
AU - Leng Goh, Eunice Tze
AU - Lloyd, Daniel G.
AU - Chalasani, Madhavi Latha S.
AU - Verma, Navin K.
AU - Prior, Stephen H.
AU - Beuerman, Roger W.
AU - Madder, Annemieke
AU - Taylor, Edward J.
AU - Singh, Ishwar
N1 - Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/3/8
Y1 - 2018/3/8
N2 - The cyclic depsipeptide, teixobactin, kills a number of Gram-positive 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.
AB - The cyclic depsipeptide, teixobactin, kills a number of Gram-positive 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.
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U2 - 10.1021/acs.jmedchem.7b01634
DO - 10.1021/acs.jmedchem.7b01634
M3 - Article
C2 - 29363971
AN - SCOPUS:85043452798
SN - 0022-2623
VL - 61
SP - 2009
EP - 2017
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 5
ER -
