ANTIMICROBIAL AND ANTI-INFLAMMATORY ACTIVITY OF BRANCHED PEPTIDES AS PROMISING ANTIBIOTICS FOR TREATING DRUG-RESISTANT BACTERIA

Antimicrobial resistance poses a severe and escalating global health challenge, reducing the effectiveness of conventional antibiotics and complicating the treatment of infectious diseases. Antimicrobial peptides (AMPs) offer promising alternatives due to their activity against multidrug-resistant pathogens and unique mechanisms of action. In this context, oral infections such as periodontal and endodontic diseases cause chronic inflammatory conditions linked to a dysbiosis of the oral microbiome and are associated with systemic inflammatory diseases, such as cardiovascular disorders. Conventional antibiotics are often ineffective due to the presence of antibiotic-resistant species within oral biofilms, such as Enterococcus faecalis in persistent endodontic infections. Moreover, the localized nature of these infections necessitates alternative treatments to minimize antibiotic use and reduce resistance development. The tetra-branched AMPs M33-D and its analogue M33i/l were studied for their potential in treating endodontic infections. M33-D and M33i/l demonstrated strong antibacterial activity against a wide range of oral pathogens, including antibiotic-resistant strains, with MICs of 0.3–1.5 µM. They rapidly permeabilized bacterial membranes, disrupted biofilms, and reduced E. faecalis colonies in dentin slices—a model for root canal irrigation—by up to 20-fold. Additionally, both peptides exhibited immunomodulatory effects, neutralizing bacterial lipopolysaccharide (LPS) and reducing the release of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) in LPS-stimulated murine macrophages and human cardiac fibroblasts. This dual activity suggests their potential to prevent systemic complications, such as atherogenesis. Furthermore, both peptides showed low toxicity to eukaryotic cells and minimal haemolytic activity, making them suitable candidates for intracanal irrigation. Beyond M33-D and M33i/l, a novel library of antimicrobial peptides was explored, providing insights into their antimicrobial efficacy, mechanisms of action, and therapeutic potential. Notably, the peptide BAMP2 showed potential for treating local infections in a mouse skin infection model. These findings underscore the potential of AMPs as innovative alternatives to traditional antibiotics for localized infections and as a strategy to combat antimicrobial resistance.