Heterogeneous efflux pump expression underpins phenotypic resistance to antimicrobial peptides

Area of Science:

• Microbiology
• Molecular Biology
• Pharmacology

Background:

• Antimicrobial resistance (AMR) poses a significant threat to global health, necessitating new therapeutic strategies.
• Conventional antibiotics are often ineffective against stationary phase bacteria, which exhibit reduced susceptibility.
• Antimicrobial peptides (AMPs) are promising due to low observed genetic resistance.

Purpose of the Study:

• To investigate the mechanisms of bacterial survival against antimicrobial peptides in stationary phase.
• To identify strategies to overcome phenotypic resistance to antimicrobial peptides.

Main Methods:

• Exposure of stationary phase *Escherichia coli* and *Pseudomonas aeruginosa* to tachyplesin.
• Analysis of phenotypic variants for genetic mutations, efflux activity, and gene expression.
• Testing the efficacy of combining tachyplesin with sertraline.

Main Results:

• Phenotypic variants of *E. coli* and *P. aeruginosa* survived tachyplesin treatment without genetic mutations.
• These variants showed increased efflux pump activity, limiting intracellular peptide accumulation.
• Differential gene regulation in outer membrane vesicle secretion, membrane modification, and protease activity was observed.
• Co-administration of tachyplesin and sertraline prevented the formation of these resistant variants.

Conclusions:

• Stationary phase bacteria can develop phenotypic resistance to antimicrobial peptides via enhanced efflux and altered cellular processes.
• Sertraline can prevent the emergence of tachyplesin-resistant phenotypic variants.
• Combination therapy with antimicrobial peptides and agents like sertraline offers a novel approach to combat antimicrobial-refractory bacteria.