Leu10-teixobactin and Ile10-teixobactin have shown comparable activity to natural teixobactin.

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-Leu-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.

The myxobacterium Myxococcus xanthus is a predatory member of the soil microfauna, able to consume bacteria (Gram-negative, Gram-positive), archaea, and fungi. Many potential prey of M. xanthus communicate amongst themselves using acyl homoserine lactones (AHLs) as quorum signals. M. xanthus cannot itself produce AHLs, but could potentially benefit by responding to exogenous AHLs produced during signaling between proximal prey. Four AHLs of different side chain length were tested and all found to delay sporulation of M. xanthus vegetative cells, and to stimulate germination of myxospores, increasing the proportion of predatory vegetative cells in the population. The predatory activity and expansion rates of M. xanthus colonies were also found to be stimulated by AHLs. Thermally inactivated AHLs had no effect on M. xanthus cells, and the response to AHLs depended (non-linearly) on the length of AHL side chain, suggesting that the effect of AHLs was mediated by specific signaling within M. xanthus, rather than being a consequence of the chemical or physical properties of AHLs. Therefore, it seems that the presence of xenic quorum signaling molecules enhances the predatory activity of M. xanthus. AHLs increase the proportion of the population capable of predation, and stimulate the motility and predatory activity of vegetative cells. We therefore propose that in the wild, M. xanthus uses AHLs as markers of nearby prey, potentially eavesdropping on the conversations between prey organisms.

We have synthesised 8 simplified, potent teixobactin analogues by replacing l-allo-enduracididine with its isosteres.