Globomycin: an interesting antimicrobial depsipeptide discovering new active analogues.

Abstract

In South Africa and other African countries infectious diseases are reported to be the main health problem and results into death. This is the reason why the pharmaceutical industry has tried to develop new antibiotics to fight these diseases. Medicinal chemists are now being challenged to fight these diseases as few drugs are available and micro-organisms have become resistant towards the available antibiotics. Gram-negative bacteria are one of those bacteria and it is difficult to inhibit it. Globomycin a “head-to-tail” cyclodepsipetide has grown interest in the pharmaceutical industry since it can specifically inhibit Gram-negative by its mode of action. Other Globomycin analogues synthesised have shown activity also against Gram-positive bacteria. In this regard new active Globomycin analogues are to be synthesised in this project to increase the activity of the antibiotic against Gram-negative and Gram-positive bacteria. Since the lipidic chain of Globomycin is aliphatic and is important for its activity, in this project it is studied what will happen on the activity of the peptide if some changes are made on the aliphatic chain such as introducing a carbonyl or sulfonyl group on the lipidic chain. The analogues were synthesised using Fmoc SPPS strategy on 2-CTC-resin as the solid support, cyclised then purified using the SEMI-PREP HPLC. This was the first synthesis of Globomycin in solid phase where cyclization was achieved by lactamization reaction. In total four analogues were synthesised namely Fmoc-Globomycin, di-Hexyl-Globomycin, Hexanoic-Globomycin and Hexanesulfonyl-Globomycin. Antimicrobial activity studies then followed where both linear and cyclic Globomycin analogues were tested against both Gram-negative and Gram-positive bacteria strains. The results illustrated that only the cyclic di-Hexyl-Globomycin analogue was active against both bacteria strains. This demonstrated that the cyclic state of the compound is very important and also the aliphatic nature. The results also agree with the work done by the Kogen group that the L-allo-Thr and L-allo-Ile units are not very important.