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Exploiting the protein O-Glycosylation pathway in opportunistic bacteria as an novel antimicrobial target


   School of Medicine, Dentistry & Biomedical Sciences

  Prof M Valvano  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

The problem. Antibiotic resistance has become a global health problem of epidemic proportions, especially for infections caused by Gram-negative bacteria. One critical need is to identify novel microbial targets that can be exploited to develop new classes of antimicrobial molecules, which could work alone, or preferably in combination, with existing antibiotics. The most effective antibiotics target central functions of bacterial cells (e.g. protein and cell wall synthesis, DNA replication and transcription). However, post-translational protein modifications have not been explored as antimicrobial targets. Protein glycosylation is a post-translational modification widespread among microorganisms. Recent work by our group has revealed that loss of protein glycosylation in our Gram-negative model bacterium, the opportunistic cystic fibrosis pathogen Burkholderia cenocepacia, dramatically reduces bacterial fitness and virulence (Mohamed et al; 2019; J. Biol. Chem. 294, 13248-13268. These findings suggest protein glycosylation can provide a novel target to reduce the burden of antibiotic resistance. The general protein glycosylation systems in bacteria target multiple membrane secreted proteins, and glycosylation defective mutants display pleiotropic phenotypes that cannot be readily correlated with the loss of glycosylation of any specific protein. For example, loss of general O-glycosylation in B. cenocepacia is essential for virulence and swimming motility, but these are complex phenotypes that denote major physiological disturbances in the glycosylation-defective mutants. However, the mechanistic bases underpinning these phenotypes are unknown. We hypothesize that loss of protein glycosylation affects the stability of unglycosylated proteins in the bacterial cell envelope resulting in an unfolded protein response leading to stress, which in turn causes dramatic reduction in cell fitness. This PhD proposal, underpinning fundamental studies at the forefront of microbial glycobiology, molecular biology and glycochemistry research, will address this hypothesis by: Elucidating the mechanism behind the physiological alterations due to loss of protein glycosylation in bacteria. Developing proof of principle that molecules inhibiting protein glycosylation can provide antimicrobial activity.

The problem. Antibiotic resistance has become a global health problem of epidemic proportions, especially for infections caused by Gram-negative bacteria. One critical need is to identify novel microbial targets that can be exploited to develop new classes of antimicrobial molecules, which could work alone, or preferably in combination, with existing antibiotics. The most effective antibiotics target central functions of bacterial cells (e.g. protein and cell wall synthesis, DNA replication and transcription). However, post-translational protein modifications have not been explored as antimicrobial targets. Protein glycosylation is a post-translational modification widespread among microorganisms. Recent work by our group has revealed that loss of protein glycosylation in our Gram-negative model bacterium, the opportunistic cystic fibrosis pathogen Burkholderia cenocepacia, dramatically reduces bacterial fitness and virulence (Mohamed et al; 2019; J. Biol. Chem. 294, 13248-13268. These findings suggest protein glycosylation can provide a novel target to reduce the burden of antibiotic resistance.

Start Date: October 2022


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