Doctoral themes 2023

Design and synthesis of membrane-disrupting sugar-based prodrugs with potential antimicrobial activity against multidrug-resistant Gram-negative bacteria 

Supervisors

Ana Marta de Matos, amamatos@fc.ul.pt

Rodrigo Almeida, rfalmeida@fc.ul.pt

Registration Institution

Faculdade de Ciências, Universidade de Lisboa

Project description

Antimicrobial resistance is one of the most urgent public health concerns of our time, with Gram-negative bacteria being some of the most difficult pathogens to target due to the presence of two lipid bilayers in their cell envelope: the inner (IM) and the outer membrane (OM). This exploratory Ph.D. project will focus on the design and synthesis of alkyl disaccharide prodrugs with the appropriate structure and physicochemical characteristics to (1) pass through the OM; (2) be cleaved by periplasm enzymatic machinery, namely peptidoglycan glycosidases (PGGs); and (3) to cause bacterial cell lysis by interacting with IM phosphatidylethanolamine (PE) once the pharmacophore is released in the periplasm. Compound design and synthesis will take place at the Carbohydrate Chemistry Lab of CQE, under the supervision of Ana Marta de Matos (Group 11 - Carbohydrate Chemistry Group (CCG)), while membrane interaction assays will be conducted at the Molecular Biophysics Lab of CQE, under the supervision of Prof. Rodrigo Almeida (Group 8 - Photoactive Molecules, Photonics and Functional Materials (MPPM)). The development and optimization of an assay able to estimate PGG hydrolysis will be carried out at the Department of Organic Chemistry, University of Sevilla (Spain), under the coordination of Prof. Óscar López for a total period of at least 4 months. The best compounds will subsequently be tested in multidrug-resistant Gram-negative bacteria for the assessment of porin passage through the OM and minimum inhibitory concentration (MIC) determination.

Keywords

Carbohydrate Chemistry

Antibiotic Development

Membrane-drug Interactions