Resumen:
Salmonella genus is a leading cause of food-borne infections with strong public
health impact and economic ramifications. The development of antimicrobial
resistance added complexity to this scenario and turned the antibiotic drug
discovery into a highly important challenge. The screening of peptides has served
as a successful discovery platform to design new antibiotic candidates. Motivated
by this, the antimicrobial and cytotoxic properties of three cruzioseptins against
Salmonella Typhimurium and RAW 264.7 murine macrophage cells, respectively,
were investigated. [K4K15]CZS-1 was the most potent antimicrobial peptide
identified in the screening step with a minimum inhibitory concentration (MIC) of
16 μg/mL (7.26 μM) and moderate cytotoxicity. From a structural point of view, in
vitro and in silico techniques evidenced that [K4K15]CZS-1 is a α-helical cationic
antimicrobial peptide. In order to capture mechanistic details and fully decipher
their antibacterial action, we adopted a multidimensional approach, including
spectroscopy, electron microscopy and omics analysis. In general lines, [K4K15]
CZS-1 caused membrane damage, intracellular alterations in Salmonella and
modulated metabolic pathways, such as the tricarboxylic acid (TCA) cycle, fatty
acid biosynthesis, and lipid metabolism. Overall, these findings provide deeper
insights into the antibacterial properties and multidimensional mode of action of
[K4K15]CZS-1 against Salmonella Typhimurium. In summary, this study represents
a first step toward the screening of membrane-acting and intracellular-targeting
peptides as potential bio-preservatives to prevent foodborne outbreaks caused
by Salmonella.
