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

Hye-Ra Lee,Hong Kyu Kim,Deok-Gyun You,Jong Kuk Park,Young Do Yoo,Gi Young Lee,Min Ja Kim,Jang Wook Sohn,Sang Yup Lee

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.

Highlights

IMPORTANCE Abuse of antibiotics often leads to increase of multidrug-resistant (MDR) bacteria, which threatens the life of human beings
Because mitochondria and bacteria share an ancestor [26] and many intracellular bacteria can replicate within host cells [27], we posited that intracellular bacteria could be killed by nucleus-encoded proteins translocated into mitochondria, which harbor an amphipathic pore-forming domain, since amphipathic alpha-helical structures have antimicrobial activity
We evaluated the efficacy of AMPR-11 in the murine model of sepsis caused by MDR bacteria, including MRSA and carbapenem-resistant Gram-negative bacteria (P. aeruginosa [carbapenem-resistant P. aeruginosa (CRPA)], K. pneumoniae [CRKP], and A. baumannii [carbapenem-resistant A. baumannii (CRAB)]), which were clinically isolated from sputum at Korea University Hospital

Summary

Introduction

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. These antibiotics have mainly been developed to cure bacterial skin infections rather than others, such as life-threatening sepsis. The lipopeptide colistin, a last-resort antibiotic that was discontinued in the 1980s because of neuro- and nephrotoxicity, is undergoing phase III trials for carbapenem-resistant Gram-negative bacteremia [12]. This situation becomes much more severe in septic patients. Orally available antimicrobial protein talactoferrin was evaluated for severe sepsis in the phase II/III OASIS trial, but the results were unsatisfactory [17]

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Results

Conclusion