טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentKaneti Galoz
SubjectOvercoming Multiple Drug Resistance and Virulence
Mechanisms in Staphylococcus Aureus
Using Oligomers of Acylated Cations
DepartmentDepartment of Biotechnology and Food Engineering
Supervisor Professor Amram Mor
Full Thesis textFull thesis text - English Version


Abstract

Staphylococcus aureus remains a major pathogen capable of causing severe illnesses, from skin and soft tissue infections to sepsis, namely due to its ability to readily acquire drug resistance. Although, the immune system is able to resolve bacterial infections, this pathogen can employ a large arsenal of toxins and evasion mechanisms to fight resolution. These key properties make both modern medicine and the host immune system less effective in resolving staphylococcal infections. Host defense peptides (HDPs) are considered a potential solution for the antibiotic resistance problem due to direct antimicrobial effect on the bacteria (alone or in combination with antibiotics) as well as indirectly by modulating the immune system. However, HDPs can also present several drawbacks especially in systemic treatments. In this respect, peptidomimetics might be more suitable. In previous studies, the peptidomimetics, oligomers of acylated lysyls (OAKs) were shown to inhibit bacterial growth in-vitro and in-vivo as well as re-sensitize mutli-drug resistant pathogens to antibiotics. Therefore, the ability of the OAK C12(ω7)KKc12K was tested for efficacy against S. aureus alone or in combination with antibiotics. The combination therapy achieved a synergistic effect resulting in up to 100% survival in the murine peritonitis sepsis model. Our data suggest that C12(ω7)KKc12K can re-sensitize S. aureus to antibiotics by inhibiting signal transduction mechanisms that result in expression of drug resistance factors. To validate this possibility, C12(ω7)KKc12K was tested for similar effects on virulence factors. Our findings suggest that the virulence conferring factors inhibited in presence of the OAK were regulated under the accessory gene regulatory (agr) quorum sensing system thus supporting the plausibility of OAK mediated signaling inhibition in S. aureus. When administered systemically to S. aureus infected mice, the OAK prevented bacterial growth in thighs of normal mice but not in thighs of neutropenic mice, thereby suggesting the involvement of the innate immune system in this effect. This report provides evidence for the OAK’s implication in immune modulation namely through activation of macrophages. Collectively, the data support the ability of C12(ω7)KKc12K to mimic both the direct and the indirect activities of HDPs.