At the onset of an infection, gram-positive bacteria attach to the host tissue using their pili, micrometer-long structures composed of hundredths of repeats of pilin proteins. Bacterial pili physically anchor the bacterium to the target cell surface, allowing it to remain attached despite the formidable host defence mechanisms. Mucus or urine flow, as well as coughing or sneezing, exert large mechanical forces on the anchored bacteria, which would readily unfold or even cleave any known protein structure; however, gram-positive bacteria have evolved an arsenal of unique molecular and chemical traits that confer their pilin proteins with unique mechanical properties, capable of resisting the immense forces reached during the initial stages of invasion.
In particular, the tip adhesin proteins in gram-positive pili—which directly mediate the interaction between the bacterium and the host cell—are often equipped with a rare internal thioester bond, which can react with Lysine residues in extracellular ligands, providing a mechanically strong and highly unreactive molecular link. Bacterial pili are recognized virulence factors, which have recently become a critical target for developing novel antibacterial treatments. Therefore, developing strategies targeted at the outstanding mechanical properties of bacterial pili emerges as an enticing therapeutical opportunity. However, since these proteins operate under large forces, which make them adopt mechanically stressed conformations, developing novel treatments that target the mechanochemistry of bacterial pili requires understanding how these proteins respond and adapt to the large mechanical forces they are exposed to, only possible with the use of novel single-molecule force spectroscopy techniques.
In this Ph.D. project, the student will use single-molecule force spectroscopy techniques to understand how the reactivity of internal thioester bonds in gram-positive adhesin pilins is regulated by mechanical forces. Based on this knowledge, the student will identify or develop new compounds or peptides aimed at blocking the reactivity of this bond, hence potentially working as an antiadhesive strategy. The student will be trained to master the use of single-molecule techniques to monitor the chemical status of individual bonds, stretched under mechanical force. The student will further acquire critical training in force spectroscopy instrumentation. Computational and mathematical modelling might also be implemented as complementary tools to interpret the molecular data.
Applicants should have, or expect to have, an integrated Master’s (e.g., MSci) with first-class honors or upper division second-class honors (2:1), or a BSc plus Master’s (MSc) degree with Merit or Distinction in Chemistry, Biochemistry, Biophysics, or a related subject.
The successful applicant will have a keen interest in interdisciplinary science, aiming to implement knowledge from Chemistry and Biophysics into the study of biological problems. A quantitative mindset is expected, and computer coding skills would be beneficial. The successful applicant will demonstrate strong interest and motivation in the subject and the ability to think critically and creatively.
Interested candidates should initially contact the supervisor (Dr. Rafael Tapia-Rojo, [Email Address Removed]) with a transcript, CV, and motivation letter expressing interest in the project. Informal inquiries are encouraged.
To be considered for the position candidates must apply via King’s Apply online application system. Details are available at:
Please indicate your desired supervisor and quote research group BPSM in your application and all correspondence.
The selection process will involve a pre-selection on documents, if selected this will be followed by an invitation to an interview. If successful at the interview, an offer will be provided in due time.