טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentZaknoon Fadia
SubjectPlasma Potentiation Against Gram-Negative Bacteria
DepartmentDepartment of Biotechnology and Food Engineering
Supervisor Professor Amram Mor
Full Thesis textFull thesis text - English Version


Abstract

Infections caused by multi-antibiotic-resistant Gram-negative bacteria (GNB) represent a serious threat to modern life style and are predicted to lead to heavy loss of lives. One of the approaches to combat such infections is to develop novel molecular structures that assist established antimicrobial agents to overcome bacterial resistance.

In this work, we designed and synthesized a novel lipopeptide-like platform, leading to a promising sequence cis-9 tetradecanoyl-ornithyl-ornithyl-decanoyl-ornithyl-amide )C14(ω5)OOc10O( which is devoid of direct antibiotic activity. Nevertheless, at low micromolar concentrations C14(ω5)OOc10O has transiently disrupted both bacterial membranes, albeit to distinct extents and consequences. Thus, the outer membrane was permeated to hydrophobic agents that normally cannot effectively cross it (hence, leading to sensitization to rifampin) and the inner membrane was mildly perturbed in a manner that dissipated the trans-membrane potential to a level manifested in malfunction of efflux pumps (hence, leading to sensitization to erythromycin) and in reduction of intracellular ATP. Such membrane-active properties are likely to explain the potent antibiotic-like activity of plasma, induced by sub-inhibitory concentrations of C14(ω5)OOc10O.

Finally, using a wound infection model, the synergistic action of C14(ω5)OOc10O and rifampin as observed in-vitro, was reenacted in-vivo, thereby suggesting a potentially useful approach to expand the currently used therapeutic strategies against GNB.