Doctoral Themes - Proposals

Azamacrocycles as a novel class of antimicrobials (CYCLACID)

Supervisors

Luis Gonçalo Alves, luis.g.alves@tecnico.ulisboa.pt

Jorge Humberto Leitão, jorgeleitao@tecnico.ulisboa.pt

Registration Institution

Instituto Superior Técnico (Universidade de Lisboa)

Project description

The treatment of infectious diseases remains an important and challenging problem as the emergence of resistant bacteria is occurring at a rapid pace endangering the efficacy of the existing antibiotics. Under these circumstances, there is a real need for the discovery of new compounds displaying antimicrobial activity. Azamacrocycle derivatives are already known to have relevant medical applications and preliminary results have shown that cyclam salts are particularly active compounds towards reference strains of S. aureus and E. coli. The current research project aims to the design and synthesis of new azamacrocycles with enhanced antimicrobial activity. The prepared compounds will be characterized by elemental analysis, NMR, FT-IR and UV-Vis spectroscopies as well as single crystal X-ray diffraction. The antimicrobial activity of the synthesized compounds against selected reference bacteria mainly of the ESKAPE group will be assessed based on CFU and/or MIC determinations. The results obtained will allow the identification of the compounds with the highest antimicrobial activity. For those, assays will be performed using multi-drug resistant strains. Depending on the results, some additional chemical modifications on the compounds might be introduced to find the best structure-activity relationship. To unveil the antimicrobial mechanisms of action, the prepared azamacrocycles with highest activities will be derivatized with magnetic beads to identify interacting proteins. Upon extraction, the bounded proteins will be processed envisaging their identification by liquid chromatography followed by mass spectrometry. Mutant strains resistant to the best cyclam derivative will be isolated for further studies on the identification of genes and proteins targeted by this new class of antimicrobial compounds.

Keywords

Synthesis, Drugs, Azamacrocyles, Antimicrobials

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