Tackling the future of antimicrobial resistance: in silico modelling of emerging beta-lactamases in complex with last resort beta-lactamase inhibitors (Póster)

BÁRBARA GHIGLIONE; MARÍA M. RODRÍGUEZ; FLORENCIA BRUNETTI; KRISZTINA M. PAPP-WALLACE; AYUMI YOSHIZUMI; YOSHIKAZU ISHII; ROBERT A. BONOMO; GABRIEL GUTKIND; SEBASTIÁN KLINKE; PABLO POWER

Online debido a la pandemia de coronavirus

Congreso; V International Congress in Translational Medicine; 2021

International Master Program in Biomedical Sciences (IMBS) (Joint Master Program between UBA and the Albert-Ludwigs University of Freiburg, Germany)

Beta-Lactamase production is the major Beta-lactam resistance mechanism in Gram-negative bacteria, while CTX-M enzymes have become the most prevalent extended-spectrum Beta-lactamases (ESBL) worldwide. The SARS-CoV-2 pandemic has exacerbated the current global crisis of antimicrobial resistance (AMR). More efficient Beta-lactamase inhibitors (BLIS) against serine Beta-lactamase (SBL) producers are urgently required. Recently, we characterized a new variant named CTX-M-151 that was isolated from a Salmonella enterica subsp. enterica serovar Choleraesuis strain infecting piglets in Japan. This variant possesses a low degree of amino acid identity with the other 246 reported CTX-Ms (63.2% to 69.7% compared to the mature proteins), and thus it may represent a new subgroup within the family or even a newly emerging type of class A Beta-lactamases. In this work, we predict the efficacy of a relatively new diazabicyclooctane (DBO) BLI, relebactam (REL), using in-silico modeling approaches from crystallographic structures of CTX-M-151 (PDB 6BN3 and 6BPF). We compared the differences in structural interaction with CTX-M-151 between REL and avibactam (AVI), a BLI that is already used and shows good inhibitory efficacy against the CTX-Ms. Compared to the X-ray crystal structures of REL bound to CTX-M-15 and KPC variants, the model of CTX-M-151/REL reveals that the C2-linked piperidine ring is positioned close to Asp240 (replaced by Gly in CTX-M-15) and therefore not affected by steric clashes with Asn104 (observed in CTX-M-15). Furthermore, mutations at Asp240 are not expected to affect interaction with REL/AVI due to the absence of bulky residues at position 104 (e.g. Trp105 in KPIs). The emergence of new resistance genes providing resistance to last-resort antibiotics, such as carbapenems and BLIS, represents a major clinical threat. After initial emergence, they are likely to remain undetected and spread silently in the human microbiota or the environment for some time. When detected, they are often already widespread. Predicting the effect of the available drug arsenal could enable us to manage of risks for future emergence events in a better way and design new DBOs with improved clinical efficacy. The data presented here provide a clue to addressing this challenge.