טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentHaykin Natan
SubjectStructure-Activity Relationships of Lipopeptide-Like
Rifampin Potentiators
DepartmentDepartment of Biotechnology and Food Engineering
Supervisor Professor Amram Mor


Abstract

It is predicted that by 2050, infectious diseases caused by antibiotic resistant bacteria will become a primary cause of death, worldwide. Moreover, efficient antibiotics are increasingly less available, particularly those that target gram negative bacteria (GNB) owing to an additional cell barrier (the outer membrane) which includes a highly dense polar monolayer of lipopolysaccharides that prevents hydrophobic antibiotics (such as rifampin) from reaching intracellular targets. Various host defense peptides and proteins (HDPs) target bacterial membranes using non-specific modes of action that depend solely on a delicate balance between their cationic and hydrophobic amino acid constituents.


Here, we studied an HDP-mimetic approach using linear and cyclic versions of short membrane active lipopeptide-like OACs. Being mildly hydrophobic, they did not inhibit bacterial growth as tested against three GNB and one gram positive strain. However, various analogs were able to efficiently sensitize GNB to rifampin and to human plasma. As expected, more hydrophobic analogs were more active. Surprisingly however, some more hydrophilic analogs revealed high potency, suggesting that optimal sensitization of GNB is achievable by combining a high hydrophobicity backbone with low hydrophobicity cationic side chains. Compared with polymyxin analogs (including SPR741, the first antibiotic potentiator drug candidate), we identified several new OACs having similar or higher potential to tackle Enterobacteriaceae infections. Also, their simplicity should be useful in better fine-tuning of molecular hydrophobicity towards distinct types of membrane activity.