|Tipo di tesi||Tesi di laurea magistrale|
|Titolo||Structure-based Drug Design e ottimizzazione di nuovi inibitori delle Beta-Lattamasi|
|Titolo in inglese||Structure-based Drug Design and optimization of novel Beta-Lactamases inhibitors|
|Struttura||Dipartimento di Scienze della Vita|
|Corso di studi||CHIMICA E TECNOLOGIA FARMACEUTICHE (D.M. 270/04)|
|Data inizio appello||2018-11-08|
|Disponibilità||Accessibile via web (tutti i file della tesi sono accessibili)|
La diffusione su scala mondiale di batteri resistenti agli antibiotici beta-lattamici attualmente disponibili in terapia rappresenta uno dei principali rischi per la salute pubblica. È necessaria un’azione immediata per contrastare la resistenza batterica verso gli antimicrobici, altrimenti tale fenomeno potrebbe diventare la prima causa di morte già entro il 2050 secondo quanto previsto dall’Organizzazione Mondiale per la Sanità (OMS).
The worldwide spread of bacteria resistant to all available antibiotics represent at the present one of the major threats to public health. Immediate actions are necessary to fight this emergency otherwise by 2050 bacterial resistance will become first cause of death, as World Health Organization (WHO) predicts. Among the several mechanisms bacteria use to respond to chemotherapy, the production of Beta-Lactamases (BLs) is a prominent one: these enzymes are able to inactivate almost all available beta-lactam antibiotics, including last resort carbapenems. BLs are classified into four different groups: class A, C and D, serine-based BLs, and class B, metallo-based BLs (MBLs). The discovery of new antibiotics and the development of new BLs inhibitors is therefore hardly necessary. Actually only BLs inhibitors active against serine-based BLs are available in therapy, while no MBLs inhibitors have been so far approved for treatment. In this scenario, my thesis work has been dedicated to the structure-based discovery of de novo inhibitor active against class A BLs and to the development of novel broad-spectrum inhibitors. First of all, the screening in vitro of a library of commercially available candidates identified by in silico analysis was performed, spectrophotometrically, against two prominent class A carbapenemases, i.e. GES-5 and KPC-2. For best inhibitors, IC50 were determined and predicted binding orientation analyzed. Additionally, a small library of six benzo[b]thiophen-2-yl-boronic acid derivates active as BLs broad-spectrum inhibitors was synthesized. The above-mentioned compounds have been in fact recently disclosed as the first acyclic boronic acids active against all BLs classes, including MBLs. The purpose was to optimize their synthetic procedures. The obtained compounds have been now directed to kinetic analysis and to x-ray crystallography studies to clarify the mechanism of action responsible of their affinity vs MBLs.