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

Parmar, Anish and Lakshminarayanan, Rajamana 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 (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). pp. 1745-2132. ISSN 0022-2623

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Abstract

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 which has shown in vivo antibacterial efficacy. There have been no in vivo evaluation studies on teixobactin analogues. In this work, we have designed and synthesized 10 new in vivo ready teixobactin analogues. These analogues showed highly potent antibacterial activity against Staphylococcus aureus, MRSA, and vancomycin-resistant Enterococci (VRE) in vitro. One analogue, D-Arg4-Leu10-teixobactin 2 was found to be non-cytotoxic in vitro and in vivo. Most importantly, in a mice model of S. aureus keratitis, topical instillation of peptide 2 decreased the bacterial bioburden (>99.0% reduction) and corneal edema significantly when compared to untreated cornea. Collectively, our results establish the excellent therapeutic potential of teixobactin analogue in attenuating bacterial infections and the associated severities.

Additional Information:PMID: 29363971
Keywords:teixobactin analogues MRSA in vivo acivity
Subjects:C Biological Sciences > C521 Medical Microbiology
Divisions:College of Science > School of Pharmacy
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ID Code:30875
Deposited On:26 Feb 2018 12:17

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