Design of peptide-based antibiotic adjuvants in the fight of antimicrobial resistance

2018 edition

N├║ria Crua Asensio

INTRODUCTION: The increasing rate of antibiotic-resistant bacteria has become a serious health threat. Thus, it is important to discover, characterize and optimize new molecules to overcome infections caused by these bacteria. One approach to tackle this problem is the use of antibiotics in combination with adjuvants. Adjuvants are bioactive compounds that enhance the antimicrobial activity of antibiotics and can minimize or even block bacteria resistance. The activity of this combined therapy is always larger sum of the individual molecules (synergy) and the kinetics is generally faster, limiting the emergence of resistant organisms.

 

Chaperones are molecules that assist the folding of proteins, including those related to antibiotic resistance. As many chaperones assemble in multimers, inhibiting the formation of these supramolecular structures may hinder the correct folding of resistance-related proteins and potentially assist the activity of antibiotics. The aim of our project is to design and develop new peptide-based compounds against chaperone multimerization that act synergistically with antibiotics.

 

MATERIALS AND METHODS: We used a combination of computational methods, including molecular dynamics simulations, phylogenetics, binding affinity and accessible surface area calculations to delineate the interfaces of chaperone multimers. We identified the amino acids that are essential to maintain the structure and designed peptides that can potentially block these interfaces. We also validated our results in vitro in E. coli by determining the minimal inhibitory concentration (MIC) of ampicillin in the presence of increasing amounts of peptide.

 

RESULTS AND CONCLUSIONS: We found a peptide candidate that shows synergistic effect when combined with ampicillin in E. coli. Even at low peptide concentrations, only half dose of ampicillin was required to kill bacteria. Moreover, the peptide-ampicillin combination was active on both model and clinically isolated strains. Future experiments are required to optimize the peptide sequence and validate its mechanism of action