Background

Resistance to all antimicrobials is rising, and the rapid development of bacterial resistance to antibiotics is one of the greatest threats to human health. Current antibiotic usage is increasing and yet only two new classes of clinically relevant antibiotics have been discovered in the last 40 years. The discovery of the new antibiotic teixobactin in 2015 has been referred to as game changing in the race for unearthing novel antibiotics where the emergence of drug resistance bacteria poses a serious threat worldwide.

Teixobactin is a cyclic depsipeptide. It belongs to a novel class of antibiotics. It kills a broad range of Gram positive bacteria including multi drug resistant bacteria and does not show any detectable resistance. Moreover, bacteria are less likely to develop resistance because it operates by at least two unique modes of action. Teixobactin binds to the highly conserved pyrophosphate motifs of multiple bacterial cell wall substrates such as lipid II and lipid III.

However, Teixobactin is unlikely to reach the clinic due to several challenges (such as gelation in aqueous conditions) posed by rigorous testing during drug development. Additionally, the synthesis of natural teixobactin is not a viable option due to lengthy and daunting synthesis and very low yield. Moreover, it requires a challenging expensive building block enduracididine.

Technology Overview

To realise the therapeutic potential of teixobactins, researchers at the University of Liverpool have developed a novel design and efficient synthesis using economical building blocks to build synthetic libraries of teixobactinan analogues. These analogues vary from natural Teixobactin in that researchers have “Engineered out” enduracididine amino acid (key bottleneck). These new molecules are easy to manufacture, retain identical or superior antibacterial activity and yet provide the means to modify shape and charge, thus offering better design for in vivo activity and development.

The new synthetic teixobactin analogues have been tested and show highly potent activity against multi drug resistant (MDR) bacteria such as Methicillin resistant Staphylococcus aureus (MRSA), Enterococcus spp. (vancomycin-resistant enterococci, VRE). MRSA and VRE have been specifically recognized as high priority pathogens by World Health Organisation (WHO). The analogues have also shown excellent teixobactin analogue activity against Gram positive clinically relevant strains and Mycobacterium smegmatis. Importantly, synthetic teixobactin offers dual advantage in vivo by clearing Staphylococcus aureus infection in mouse keratitismodel (cornea) and reducing edema significantly.

Researchers have also, for the first time, mapped the teixobactin analogues establishing which of the DL-amino acids are critical for antimicrobial activity. They have produced novel highly active teixobactin analogues showing the same or better activity than the natural compound.

Benefits

Synthetic teixobactins have shown many superior features including:

• The unique library of diverse compounds allows for future development of therapeutic drugs.
• Researchers have not detected any bacterial resistance against synthetic teixobactins.
• The molecules are commercially viable because these required shorter synthesis and use economical commercially available building blocks.
• The new synthesis method is highly efficient.
• Identical or superior potency in killing MRSA than natural teixobactin and six times superior potency in killing MRSA than Vancomycin.
• Highly potent activity against VRE.
• Very good safety in mammalian cells and no haemolysis up to tested concentration of 250µg/ml, while MIC was less than 1 µg/ml.
• Similar potency to Moxifloxacin (clinically used antibiotics) in clearing S. aureus infection in mice eyes. Importantly synthetic teixobactin reduces the edema (swelling) in eyes which was not the case for Moxifloxacin.

Applications

The market opportunity is a new design of synthetic teixobactins which are cost effective and have equal or superior potency to natural teixobactins. Teixobactins could be used to treat infections from MDR pathogens such as Methicillin resistant Staphylococcus aureus (MRSA), Enterococcus spp. (vancomycin-resistant enterococci, VRE) as well as bacterial biofilm infections.

Opportunity

The University is seeking to engage partners to help explore the topical and systemic application of synthetic teixobactin analogues.