The Design of Alapropoginine, a Novel Conjugated Ultrashort Antimicrobial Peptide with Potent Synergistic Antimicrobial Activity in Combination with Conventional Antibiotics.

Ali Salama,Ammar Almaaytah,Rula M Darwish

doi:10.3390/antibiotics10060712

Abstract

(1) Background: Antimicrobial resistance represents an urgent health dilemma facing the global human population. The development of novel antimicrobial agents is needed to face the rising number of resistant bacteria. Ultrashort antimicrobial peptides (USAMPs) are considered promising antimicrobial agents that meet the required criteria of novel antimicrobial drug development. (2) Methods: Alapropoginine was rationally designed by incorporating arginine (R), biphenylalanine (B), and naproxen to create an ultrashort hexapeptide. The antimicrobial activity of alapropoginine was evaluated against different strains of bacteria. The hemolytic activity of alapropoginine was also investigated against human erythrocytes. Finally, synergistic studies with antibiotics were performed using the checkerboard technique and the determination of the fractional inhibitory index. (3) Results: Alapropoginine displayed potent antimicrobial activities against reference and multi-drug-resistant bacteria with MIC values of as low as 28.6 µg/mL against methicillin-resistant S. aureus. Alapropoginine caused negligible toxicity toward human red blood cells. Moreover, the synergistic studies showed improved activities for the combined conventional antibiotics with a huge reduction in their antimicrobial concentrations. (4) Conclusions: The present study indicates that alapropoginine exhibits promising antimicrobial activity against reference and resistant strains of bacteria with negligible hemolytic activity. Additionally, the peptide displays synergistic or additive effects when combined with several antibiotics.

Highlights

(4) Conclusions: The present study indicates that alapropoginine exhibits promising antimicrobial activity against reference and resistant strains of bacteria with negligible hemolytic activity
Several regional and international health organizations have been consistently reporting the emergence of pan-drug-resistant (PDR) Gram-negative bacteria displaying resistance against the most powerful antimicrobial agents still available in the clinic such as colistin [3,4,5]
This situation is only worsened by the fact that the pharmaceutical industry has made little contribution to the development of antimicrobials in recent decades and its pipelines remain dry with only fewer classes of antimicrobial agents managing to reach the clinic [6,7]

Summary

Introduction

Several regional and international health organizations have been consistently reporting the emergence of pan-drug-resistant (PDR) Gram-negative bacteria displaying resistance against the most powerful antimicrobial agents still available in the clinic such as colistin [3,4,5]. This situation is exacerbated by the recent COVID-19 pandemic which swept all over the globe and shifted the focus of all health authorities, governments, and pharmaceutical companies on developing vaccines and antiviral medications to tackle the COVID-19 pandemic and overshadowing the issue of AMR. There is a significant need to develop new classes of antimicrobial agents capable of eradicating the escalating number of MDR and PDR strains of bacteria

Objectives

Methods

Results

Conclusion