Romo1-Derived Antimicrobial Peptide Is a New Antimicrobial Agent against Multidrug-Resistant Bacteria in a Murine Model of Sepsis

mBio. 2020 Apr 14;11(2):e03258-19. doi: 10.1128/mBio.03258-19.

Abstract

To overcome increasing bacterial resistance to conventional antibiotics, many antimicrobial peptides (AMPs) derived from host defense proteins have been developed. However, there are considerable obstacles to their application to systemic infections because of their low bioavailability. In the present study, we developed an AMP derived from Romo1 (AMPR-11) that exhibits a broad spectrum of antimicrobial activity. AMPR-11 showed remarkable efficacy against sepsis-causing bacteria, including multidrug-resistant strains, with low toxicity in a murine model of sepsis after intravenous administration. It seems that AMPR-11 disrupts bacterial membranes by interacting with cardiolipin and lipid A. From the results of this study, we suggest that AMPR-11 is a new class of agent for overcoming low efficacy in the intravenous application of AMPs and is a promising candidate to overcome multidrug resistance.IMPORTANCE Abuse of antibiotics often leads to increase of multidrug-resistant (MDR) bacteria, which threatens the life of human beings. To overcome threat of antibiotic resistance, scientists are developing a novel class of antibiotics, antimicrobial peptides, that can eradicate MDR bacteria. Unfortunately, these antibiotics have mainly been developed to cure bacterial skin infections rather than others, such as life-threatening sepsis. Major pharmaceutical companies have tried to develop antiseptic drugs; however, they have not been successful. Here, we report that AMPR-11, the antimicrobial peptide (AMP) derived from mitochondrial nonselective channel Romo1, has antimicrobial activity against Gram-positive and Gram-negative bacteria comprising many clinically isolated MDR strains. Moreover, AMPR-11 increased the survival rate in a murine model of sepsis caused by MDR bacteria. We propose that AMPR-11 could be a novel antiseptic drug candidate with a broad antimicrobial spectrum to overcome MDR bacterial infection.

Keywords: AMPR-11; antimicrobial peptide; drug resistance; multidrug-resistant bacteria; peptide antibiotics; sepsis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravenous
  • Animals
  • Anti-Infective Agents / therapeutic use
  • Antimicrobial Cationic Peptides / therapeutic use*
  • Bacteria / drug effects*
  • Bacterial Outer Membrane / drug effects
  • Biofilms / drug effects
  • Disease Models, Animal
  • Drug Resistance, Multiple, Bacterial*
  • HeLa Cells
  • Humans
  • Male
  • Membrane Proteins / chemistry
  • Membrane Proteins / therapeutic use*
  • Mice
  • Mice, Inbred C57BL
  • Microbial Sensitivity Tests
  • Mitochondrial Proteins / chemistry
  • Mitochondrial Proteins / therapeutic use*
  • Sepsis / drug therapy*

Substances

  • Anti-Infective Agents
  • Antimicrobial Cationic Peptides
  • Membrane Proteins
  • Mitochondrial Proteins
  • ROMO1 protein, human