Molecular structure of new teixobactin analogues explained, paves way in the fight against antimicrobial resistance

0
1220
Scientists move a step closer to developing major new drugs in fight against antimicrobial resistance

bacteria-426997_1280

In 2015, Teixobactin created a buzz as a naturally found antibiotic which easily combated bacteria without any detectable resistance. The strain of Teixobactin found had been isolated from soil samples collected using a device known as the iChip by scientists from Northeastern University, USA.

The team at the University of Lincoln, UK, had previously produced two synthetic derivatives of teixobactin – which were hailed as a ‘game-changer’ in the fight against antimicrobial resistance – and the researchers have now documented the molecular make-up of the antibiotic. Not only that, this new study sheds light on the relationship between the antibiotic’s molecular structure and its biological activity.

This advancement is an important next step in understanding how the different derivatives of teixobactin function and which structural constituents of the molecule are required to combat and successfully destroy drug-resistant bacteria.

“We successfully defined the molecular structure of seven teixobactin analogues”, Dr Ishwar Singh from the School of Pharmacy at Lincoln University explained. “This enabled us to understand the importance of the individual amino acids within the antibiotic, and to understand the contribution they each make to the molecular structures of teixobactin. We found that one particular amino acid (D‐Gln4) is essential and another (D‐Ile5) is important for maintaining the disordered structure of teixobactin, which is imperative for its biological activity.”

(a) (left) Structure of teixobactin. (b) (right) Structure of the teixobactin analogue 1 showing the bonds to be cleaved for the synthesis routes A (in blue) and B (in red) and the structural differences (in green).
(a) (left) Structure of teixobactin. (b) (right) Structure of the teixobactin analogue 1 showing the bonds to be cleaved for the synthesis routes A (in blue) and B (in red) and the structural differences (in green). This picture is licensed under a Creative Commons Attribution 3.0 Unported Licence.

Dr Singh’s team prepared various derivatives of teixobactin which were then biologically tested by Dr Edward Taylor, of the Licoln’s School of Life Sciences, to explore the relationship between teixobactin’s molecular structure and its biological activity.

The team has discovered that the molecular assembly of teixobactin directly influences its antimicrobial qualities and its efficacy at fighting pathogens. They found that teixobactin’s relatively unstructured molecular make-up was strategic to the biological activity of the antibiotic, with more structured deviations proving to be inactive. They also distinguished a way to maintain this ‘disorder’ when synthesising the different derivatives.

Dr Taylor said: “By exploring the structures of different versions of teixobactin we are, for the first time, able to begin to understand how this molecule works. This knowledge will enable us to produce different forms of teixobactin more easily and on a larger scale with potentially better pharmaceutical properties.”

With continuing high expectations from teixobactin, this work is a significant step in identifying the key molecular units of teixobactin that are essential to ensure its effectiveness as a commercial drug as as a stepping stonetowards an in depth study of teixobactin, its analogues and the quest for synthesising similar molecules..

The study has been published in the Royal Society of Chemistry journal, Chemical Communications.