Nuevos inhibidores de β-lactamasas frente a patógenos gram negativos multirresistentes

Resumo

Acinetobacter baumannii, Pseudomonas aeruginosa and the order Enterobacterales are categorised as critical priority pathogens for the development of new antimicrobials. The most widely used group of antibiotics is the β-lactam group. Cephalosporins and carbapenems have the highest spectrum of activity. The use of these antibiotics is compromised by the emergence and spread of extended-spectrum β-lactamases (ESBLs) and carbapenemases. One option to maintain the activity of these β-lactams is the use of β-lactamase inhibitors. In this Thesis, the good activity of LN-1-255, a penicillin sulphone in the preclinical phase, was determined against the OXA-48 carbapenemase of Enterobacterales and the carbapenem-hydrolysing class D β-lactamases (CHDLs) of A. baumannii. The latter was also demonstrated in in vivo trials, where the combination of imipenem and LN-1-255 significantly decreased the bacterial load. Moreover, both LN-1-255 and two derivatives of LN-1-255 were shown to be able to inhibit PDC-1 of P. aeruginosa, allowing the activity of ceftazidime to be restored. Finally, the efficacy of the recently approved imipenem/relebactam, and cefepime/zidebactam and cefepime/taniborbactam combinations, in clinical phase III, was demonstrated in a national multicentre study of carbapenemase-producing Enterobacterales.