Assessing defensive and offensive aspects of bacterial infection using computer simulations

Abstract

Bacterial infections pose a significant problem in the modern world. An alarming increase in multi-drug resistant bacteria has become a serious source of concern, with a steep rise in reported cases of sepsis and deaths related to bacterial infection. New drugs are necessary for the treatment and management of bacterial infection, including new broad spectrum antibiotics capable of killing multi-drug resistant bacteria as well as anti-septic drugs for the management of severe bacterial infections.

This thesis investigates antimicrobial peptides, that have shown promise as antibiotics due to their broadspectrum range. They are of particular interest as they do not target specific proteins that can be easily altered through point mutations, but rather the bacterial membrane itself, making the emergence of resistance rarer. Understanding the structure-function relationship of these peptides could help design new antibiotics capable of killing resistant strains of bacteria. The other aspect investigated in this thesis is the function of immune receptors TLR4 and CD14, both part of the TLR4 signalling pathway. In sepsis, it is believed that over-activation of the TLR4 pathway contributes to the over-production of pro-inflammatory cytokines that lead to septic shock. Understanding the behavior of these receptors in different environments is important as the identification of potential drug targets could be beneficial to the development of immunomodulatory drugs and the prevention of septic shock. Overall this thesis covers both the offensive aspect of dealing with bacterial infections, eradicating bacteria, and the defensive aspect, understanding the innate immune system and modulating its activity to prevent sepsis associated death.

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ORCID for Syma Khalid: orcid.org/0000-0002-3694-5044

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