Effects of the resistance mechanism against colistin through MCR against other cationic AMPs

MATURANA PATRICIA; HOLLMANN AXEL; MAFFIA, PAULO

Rosario

Congreso; L Reunión Anual de la Sociedad Argentina de Biofísica; 2022

Sociedad Argentina de Biofisica

It was recently described that E. coli clinical isolates from an Argentinean hospital,harboring the mcr-1 gen displayed colistin-resistant phenotype by the replacement oflipid A with the PEtN-4´-lipid A, mediated by phosphoethanolamine transferase enzymeencoded in MCR plasmid. In this work, using two resistant isolates, carrying the MCRplasmid, we evaluated the effects that this surface modification could have against othercationic peptides. In this sense, first, we evaluated the effect that the addition of PEtN-4´to lipid A induces in the zeta potential of the isolates, taking advantage that EDTA inhibitsthe activity of the enzyme responsible for the surface modification. Our results indicatethat the Lipid A substitution induces a significant reducción of the negative bacterialsurface charges. Then the effects on the antibacterial activity of two “de novo” cationicpeptides P5 and P6.2 were evaluated in the clinical isolates and sensible reference E. coliATCC 25923 with and without EDTA. In the absence of EDTA both clinical isolates showedan increase in the MIC values in comparison with the results in presence of EDTA, withoutchanges on reference strain. With the aim of better characterization, permeability assaysinduced by the peptides were carried out in both clinical isolates in the presence andabsence of EDTA, showing that the changes observed on the surface charges affect theability of the peptides to permeabilize the external membrane of the bacteria. Besidesfurther experiments should be carried out, it was proved that this surface modificationaffects not only colistin but other cationic peptides. The fact that modification throughsubstitution of lipid A is plasmid-encoded represents an important concern in the futureof antimicrobial peptide drug development.