engleski

Algorithmic and knowledge-based modifications of cell-penetrating peptide leading to its improved physicochemical properties and antimicrobial activity

It is clear that bacteria will continue to develop various mechanisms of resistance against antibiotics, so it is important to keep searching for new drug molecules. There are four major mechanisms of antibiotic action against bacteria: interference with cell wall synthesis, inhibition of protein synthesis, inhibition of nucleic acids synthesis, disturbing metabolic pathways. Disruption of the bacterial membrane can be considered as a fifth major mechanism of antibiotic action. Antimicrobial peptides (AMPs) are ancient weapons against bacteria that are produced in both the animal and plant kingdom. These small cationic molecules interact with bacterial surfaces and the result is mainly permeabilization of their membranes which naturally leads to bacterial death. Since they are not as specific as other antibiotic, bacteria cannot develop resistance as quickly as for classical antibiotics. Differences between host and microbial membranes are very important for the selectivity of AMPs. This is also the case for cell penetrating peptides (CPPs), peptides that are able to cross the plasma membrane of eukaryotic cells. Some CPPs are also AMPs and vice-versa. MAP is an example of a cationic and amphiphatic CPP with antimicrobial properties which is active against Gram-negative and Gram- positive bacteria. Can it be converted into highly active AMP by MUTATOR suggested amino acid substitutions (http://split4.pmfst.hr/mutator/)? The novel sequence MAPL6A has been synthesized and shown to have good activity and selectivity against the Gram negative bacterium E. coli. It has significantly reduced haemolytic activity with respect to the parent MAP peptide. It also inhibits growth of S. aureus.

antimicrobial peptide; cell-penetrating peptide; mutator algorithm

magistarski rad (MSc degree thesis)