Curbing gastrointestinal infections by defensin fragment modifications without harming commensal microbiota

Area of Science:

• Microbiology
• Infectious Diseases
• Drug Discovery

Background:

• Multidrug-resistant pathogens, particularly ESKAPE bacteria, pose a significant global health threat, leading to untreatable infections.
• The rise of antimicrobial resistance necessitates the development of novel therapeutic strategies.

Purpose of the Study:

• To develop and characterize a novel antimicrobial peptide, Pam-3, with potent activity against multidrug-resistant bacteria and biofilms.
• To evaluate the efficacy and safety of Pam-3 in preclinical infection models.

Main Methods:

• Pam-3, derived from human β-defensin 1, was synthesized and tested for antimicrobial and antibiofilm activity in vitro.
• Mechanism of action was investigated, focusing on membrane integrity disruption.
• Efficacy was assessed in mouse models of Salmonella and Citrobacter infections, with analysis of microbiota impact.

Main Results:

• Pam-3 demonstrated significant antimicrobial activity against multidrug-resistant ESKAPE pathogens and eradicated pre-formed biofilms in vitro.
• The peptide functions by disrupting bacterial membrane integrity.
• No drug resistance developed upon prolonged exposure.
• In vivo studies showed Pam-3 effectively reduced Salmonella and Citrobacter infections in mice without disrupting the gut microbiota.

Conclusions:

• Defensin-derived antimicrobial peptides represent a promising new class of agents for combating multidrug-resistant bacteria.
• Pam-3 is a potent candidate, exhibiting broad-spectrum activity, biofilm eradication, and microbiota preservation, offering a potential alternative to conventional antibiotics.