(a) Gram-negative bacteria include some of the most severe human pathogens, including Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella, Enterobacteria and more. A common trait between these is the possession of an outer lipidic membrane, which notably protects them from antibiotics. Accordingly, elucidation the molecular details of the formation and maintenance of this outer membrane could pave the way towards the development of new antibiotics.
(b) The student will employ structure-based drug design approaches to develop inhibitors of the machinery involved in OM biogenesis. Following this, they will be trained in the synthesis of such inhibitors, and their chemical characterization. Next, they will gain experience in the biochemical characterization of their interaction with the targeted machinery, and will learn how to determine the structure of these complexes by cryo-EM. Finally, they will have the opportunity to be involved in the efficacy characterization of such chemicals for the treatment of antibiotic-resistant bacterial infection.
(c) The overall aim of this project is to develop and characterize small-molecule inhibitors of the MLA pathway. These will be critical to elucidate its molecular mechanism, and could be used for the treatment of antibiotic-resistant bacterial strains.
(d) The objectives for the PhD are:
– Year 1: Identification of potentially druggable pockets on the structures of the various MLA components (IM complex, OM complex, periplasmic transporter); in-silico screening of potential inhibitors for the most promising pockets; Chemical synthesis of the corresponding molecules
– Year 2: Biochemical and biophysical validation of the compounds’ interaction with their respective binding partners.
– Year 3: Structural elucidation of the MLA components bound to inhibitors, by cryo-EM.
– Year 4: Characterization of the inhibitors’s effect on bacterial growth, and on antibiotic resistance.
(e) The 3-month rotation project focuses on developing small-molecule inhibitors targeting the MLA pathway involved in outer membrane (OM) biogenesis in Gram-negative bacteria, a major contributor to antibiotic resistance. The student will use structure-based drug design to identify druggable pockets and screen for candidate inhibitors, followed by chemical synthesis and characterisation of selected compounds. They will gain experience in biochemical assays to evaluate compound binding and be introduced to cryo-EM methods for structural studies. This project provides interdisciplinary training across computational chemistry, medicinal chemistry, and structural biology, contributing to the development of new strategies to combat antibiotic-resistant bacterial infections.
