Antibiotic-resistant bacteria show widespread collateral sensitivity to antimicrobial peptides

Area of Science:

• Microbiology
• Biochemistry
• Drug Discovery

Background:

• Antimicrobial peptides (AMPs) offer a potential alternative to conventional antibiotics.
• The relationship between resistance to small-molecule antibiotics and bacterial sensitivity to AMPs is largely unknown.
• Understanding this relationship is crucial for developing novel antimicrobial strategies.

Purpose of the Study:

• To investigate whether antibiotic resistance in bacteria confers cross-resistance or collateral sensitivity to antimicrobial peptides.
• To identify specific mutations and mechanisms underlying these resistance/sensitivity phenotypes.
• To explore the potential of antimicrobial peptide-antibiotic combinations against multidrug-resistant bacteria.

Main Methods:

• Systematic susceptibility testing of 60 antibiotic-resistant Escherichia coli strains against 24 antimicrobial peptides.
• Identification of clinically relevant multidrug-resistance mutations.
• Analysis of regulatory changes affecting bacterial outer membrane lipopolysaccharide composition.

Main Results:

• A high frequency of collateral sensitivity was observed in antibiotic-resistant bacteria towards antimicrobial peptides, with cross-resistance being rare.
• Specific multidrug-resistance mutations were found to enhance bacterial sensitivity to antimicrobial peptides.
• Changes in lipopolysaccharide composition were identified as a contributing factor to collateral sensitivity.

Conclusions:

• Antibiotic-resistant bacteria frequently exhibit collateral sensitivity to antimicrobial peptides, presenting therapeutic opportunities.
• Antimicrobial peptide-antibiotic combinations can enhance efficacy against multidrug-resistant bacteria and mitigate resistance evolution.
• The antimicrobial peptide glycine-leucine-amide demonstrated a significant reduction in antibiotic resistance levels when used as an adjuvant.