Lauretao in Scienze Biologiche. Dal 2011, Ricercatore in Microbiologia Generale presso il Dipartimento di Biologia e Biotecnologie di Sapienza Università di Roma.
“In passato avevo già avuto fondi dall’Istituto Pasteur per un progetto triennale per ricercatori under 40. Quel finanziamento mi ha permesso di studiare alcuni meccanismi molecolari rilevanti per la vitalità delle cellule batteriche e per la resistenza agli antibiotici, ed ha portato all’identificazione del composto antibatterico che sarà oggetto di studio nel progetto appena attivato (biennio 2018 – 2019). Lo scopo è quello di sviluppare molecole e approcci terapeutici per aumentare l’efficacia di vecchi antibiotici che, a causa della diffusione di ceppi batterici resistenti, rischiano di non poter più essere utilizzati per il trattamento delle infezioni batteriche”.
Functional characterization and pharmacological inhibition of colistin resistance in
The old antibiotic colistin represents our last-line treatment option against many multi-drug resistant Gram-negative bacteria. However, reports of colistin resistance in clinical isolates are rising, calling for alternative therapeutic strategies and/or efforts to preserve the clinical efficacy of colistin.
Aminoarabinosylation of LPS is a common colistin resistance mechanism in Gram-negative bacteria, and recent evidences indicate that this LPS modification is strictly required for the development of colistin resistance in Pseudomonas aeruginosa, one of the most dreaded opportunistic pathogens for which effective therapeutic options are very limited. By taking advantage of recently-published structural and functional information on the last enzymatic step of LPS aminoarabinosylation, we carried out a docking-based virtual screening of an in house natural compounds library, which led to the identification of a putative inhibitor of LPS aminoarabinosylation showing significant synergism with colistin against a reference P. aeruginosa colistin-resistant isolate. This project is aimed at further development and validation of this inhibitor, through structurebased design of derivatives with improved binding affinity, and evaluation of their colistin synergistic activity and cytotoxicity on eukaryotic cells in vitro. The range of activity of the most promising compounds will be then assessed on a collection of P. aeruginosa colistin resistant clinical isolates, as well as on other Gram-negative pathogens. Moreover, the inhibition of LPS aminoarabinosylation in inhibitor-treated bacteria will be confirmed by mass spectrometry. Finally, the colistin synergistic activity of selected compounds will be verified in vivo using a simple animal model of infection. In parallel, the cellular pathways involved in the development of high-level adaptive resistance to colistin in P. aeruginosa will be investigated by functional genomics, with the final goal to identify new potential targets for the design of additional colistin synergists with different mechanisms of action. The expected deliverables of this project, in terms of both antibacterial compounds and information, would provide new pharmacological opportunities to extend the clinical lifetime of colistin that, at present, represents our last resort for many recalcitrant Gram-negative infections.