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.