Therapeutic Effects of Inhibitor of ompA Expression against Carbapenem-Resistant Acinetobacter baumannii Strains.

Seok-Hyeon Na,Hyejin Jeon,Yoo-Jeong Kim,Je-Chul Lee,Man-Hwan Oh,Ill-Young Lee,Mingi Chu

doi:10.3390/ijms222212257

Abstract

The widespread of carbapenem-resistant Acinetobacter baumannii (CRAB) is of great concern in clinical settings worldwide. It is urgent to develop new therapeutic agents against this pathogen. This study aimed to evaluate the therapeutic potentials of compound 62520, which has been previously identified as an inhibitor of the ompA promoter activity of A. baumannii, against CRAB isolates, both in vitro and in vivo. Compound 62520 was found to inhibit the ompA expression and biofilm formation in A. baumannii ATCC 17978 at sub-inhibitory concentrations in a dose-dependent manner. These inhibitory properties were also observed in clinical CRAB isolates belonging to sequence type (ST) 191. Additionally, compound 62520 exhibited a bacteriostatic activity against clinical clonal complex (CC) 208 CRAB isolates, including ST191, and ESKAPE pathogens. This bacteriostatic activity was not different between STs of CRAB isolates. Bacterial clearance was observed in mice infected with bioimaging A. baumannii strain 24 h after treatment with compound 62520. Compound 62520 was shown to significantly increase the survival rates of both immunocompetent and neutropenic mice infected with A. baumannii ATCC 17978. This compound also increased the survival rates of mice infected with clinical CRAB isolate. These results suggest that compound 62520 is a promising scaffold to develop a novel therapeutic agent against CRAB infections.

Highlights

Introduction published maps and institutional affilAcinetobacter baumannii is one of the problematic ‘ESKAPE’ pathogens, known to be the leading cause of nosocomial infections and to develop multidrug resistance (MDR) [1].This gram-negative, non-fermenting opportunistic pathogen causes a variety of nosocomial infections—including pneumonia, wound and urinary tract infections, meningitis, and bacteremia—in severely ill patients admitted to intensive care units [2,3,4]
Compound 62520 Is a Hit Small Molecule Inhibiting the ompA Promoter Activity of Reporter strain OH101, carrying a single copy of the ompA promoter and an open reading frame of ermAM fusion in the chromosome, was constructed to determine whether compound 62520 inhibited the ompA promoter located in the chromosome
95 chemical compounds that showed structural similarity with compound 62520 were selected from the chemical library of the Korea Chemical Bank, and their ability to inhibit the growth of the OH101 strain in a culture medium containing erythromycin was determined

Summary

Introduction

Acinetobacter baumannii is one of the problematic ‘ESKAPE’ pathogens, known to be the leading cause of nosocomial infections and to develop multidrug resistance (MDR) [1]. This gram-negative, non-fermenting opportunistic pathogen causes a variety of nosocomial infections—including pneumonia, wound and urinary tract infections, meningitis, and bacteremia—in severely ill patients admitted to intensive care units [2,3,4]. Colistin and tigecycline still work effectively for the treatment of CRAB infections, but resistance to these antimicrobial agents has increased in clinical A. baumannii isolates [8,9]. The wide spread of drug-resistant A. baumannii strains, and the therapeutic difficulty associated iations

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