Evaluation of the in vitro effect of analogues CR22-DKs12, CR22-BR04 and CR21-BR11 of the antimicrobial peptide B1CTcu5 in the inhibition of efflux pumps against macrophage infection by Mycobacterium tuberculosis.

Abstract

Tuberculosis, a disease that primarily affects the lungs, represents one of the highest rates of death caused by a single pathological agent worldwide. The World Health Organization estimated, in 2021, that the disease, caused by infection with the Mycobacterium tuberculosis bacillus (Mtb), was responsible for the deaths of 1.6 million people, 1.4 million of whom were HIV negative and 187,000 seropositive. As treatment, the use of first-line drugs such as Rifampicin and Isoniazid is established, however studies prove the high rate of resistance to these antibiotics among bacilli, making it necessary to use second-line antibiotics, which also already have a certain rate of resistance. . To combat antibiotic resistance, the search for substances with the capacity to inhibit different efflux pumps (IBE) has become a very interesting field of study. Seeking new strategies to combat tuberculosis, antimicrobial peptides (AMPs), substances with a diverse group of molecules composed of short peptide sequences, are effective against potentially pathogenic bacterial infections, presenting great importance in the context of multidrug resistance to antibiotics. Previous studies indicate that the B1CTcu5 peptide, belonging to the Brevinin-1 family, has great potential against Mtb. However, due to its pharmacokinetic instabilities, our research group, as part of Cesar Roque Borda's doctoral project (FAPESP #2020/16573-3 and #2021/14603-5), developed analogues of this peptide, which showed better action and greater specificity than Isoniazid. The present study aims to evaluate and quantify the inhibitory activity of efflux pumps in intramacrophagic Mtb of B1CTcu5 analogues, thus aiming to qualify a potential therapeutic strategy against resistant Mtb.