Teixobactin be used to develop more effective,

Teixobactin is a highly potent depsipeptide antibiotic. Its very effective against drug resistant pathogens e.g. (MRSA) and Mycobacterium tuberculosis. IT contains a rare L-allo-enduracididine residue (red) which makes it incredibly difficult to synthesis. Replacement of this L-allo-End10 were investigated with alternative residues giving higher yields.
Analogues 1-8 were tested against 3 Gram positive bacteria and compared with the effectiveness of the original teixobactin and the results were recorded.
Development of analogues
The L-allo-End10 residue is said to be important for drug activity but the protected synthesis of the L-allo-End10 Teixobactin gave a 3.3% overall yield. Analogues of the drug using similar residues were synthesized, these gave much greater yields and still showed promising biological activity against bacteria.
8 analogues (right) were synthesized using readily available materials producing drugs with the L-allo-End10 residue replaced with isosteres and a study was started into the best replacement for the original.
The hypothesis was that the molecules who’s residues were close isosteres to the original would be the most potent.
Molecule 2 showed the most promising results with the lowest MIC against every bacterium tested followed by 1 then 3 respectively, these results are to be expected as these molecules are the most similar isosteres to the original L-allo-End10 residue, thus supporting the original hypothesis.
The knowledge gained from this experiment can be used to further develop more potent analogues and make more effective drugs. A large pool of other analogues can be made and tested from the simple synthesis of the amine precursors described (right). This along with the higher yields and the cheaper production of the analogues can also be used to develop more effective, lower cost drugs for the public and potentially make higher profits for drug companies who decide to produce analogues similar to these.
General synthesis of the guanidine analogues is done very rapidly by a one step process from the amine precursor. This can also be done to make secondary amides and a variety of A.A. side chains leading to a vast array of potential drugs.
8 analogues for L-allo-End10 Teixobactin were synthesized and tested against 3 types of gram positive bacteria. Three compounds in particular showed very promising results (1,2 and 3) where the replacement residues were Lysine, Homoarginine and Norarginine. In addition to this there was little to distinguish the guanidine side chains to the amine counterparts, showing there is relative flexibility in the structure when it comes the activity of these drugs. The findings from this investigation could majorly help in the development of better multi drug resistant bacteria.