|M.Sc Student||Pozdnyakov Igor|
|Subject||Erythromycin Potentiation Against Gram-Negative Bacteria|
|Department||Department of Biotechnology and Food Engineering||Supervisor||Professor Amram Mor|
The World Health Organization (WHO) has declared antimicrobial resistance a priority health issue. Resistance development is not a matter of if but of when, making the development of new antibiotics unprofitable business for pharma companies. Erythromycin, the first member of macrolide family of antibiotics is highly effective against most gram-positive bacteria (GPB) but struggles to inhibit gram-negative bacteria (GNB) due to reduced accumulation within the cytoplasm. Antimicrobial peptides (AMPs), cationic and hydrophobic structures, are attracted to negatively charged bacterial membranes then disrupt it by multiple non-specific modes of action, making it difficult for bacteria to develop resistance. In this work, we assessed the importance of cyclization of chemical mimics of natural AMPs, termed Oligo Acyl Cations (OAC).
Being mildly hydrophobic, these cyclic OACs did not inhibit bacterial growth as tested against three GNB in LB medium. However, various analogs were able to potentiate erythromycin and human plasma antimicrobial components against these bacteria. Such indirect antibacterial activity was found to correlate with increased backbone acyls hydrophobicity. Mechanistic studies suggest that cyclic OACs lead to transient destabilization of both cytoplasmic- and outer-membrane, thereby promoting both cell-wall penetration and cytoplasmic accumulation of erythromycin. Thus, this cyclic platform may be useful for development of lead erythromycin potentiator candidates due to its higher potency and simplicity compared to currently ongoing clinical trial drugs, such as the polymyxin B derivative, SPR741.