In Vitro and In Vivo Activity of AS101 against Carbapenem-Resistant Acinetobacter baumannii.

Tsung-Ying Yang,Liang-Chun Wang,Wei-Chun Hung,Po-Liang Lu,Lin Lin,Sung-Pin Tseng,Heather Nokulunga Dlamini

doi:10.3390/ph14080823

Abstract

The increasing trend of carbapenem-resistant Acinetobacter baumannii (CRAB) worldwide has become a concern, limiting therapeutic alternatives and increasing morbidity and mortality rates. The immunomodulation agent ammonium trichloro (dioxoethylene-O,O′-) tellurate (AS101) was repurposed as an antimicrobial agent against CRAB. Between 2016 and 2018, 27 CRAB clinical isolates were collected in Taiwan. The in vitro antibacterial activities of AS101 were evaluated using broth microdilution, time-kill assay, reactive oxygen species (ROS) detection and electron microscopy. In vivo effectiveness was assessed using a sepsis mouse infection model. The MIC range of AS101 for 27 CRAB isolates was from 0.5 to 32 µg/mL, which is below its 50% cytotoxicity (approximately 150 µg/mL). Bactericidal activity was confirmed using a time-kill assay. The antibacterial mechanism of AS101 was the accumulation of the ROS and the disruption of the cell membrane, which, in turn, results in cell death. The carbapenemase-producing A. baumannii mouse sepsis model showed that AS101 was a better therapeutic effect than colistin. The mice survival rate after 120 h was 33% (4/12) in the colistin-treated group and 58% (7/12) in the high-dose AS101 (3.33 mg/kg/day) group. Furthermore, high-dose AS101 significantly decreased bacterial population in the liver, kidney and spleen (all p < 0.001). These findings support the concept that AS101 is an ideal candidate for further testing in future studies.

Highlights

Antibacterial Efficacy of AS101 against carbapenem resistance in A. baumannii (CRAB) Clinical Isolates. Among these 27 CRAB clinical isolates, high resistant ratios were found in the following different classes of antibiotics: meropenem (27/27, 100%), levofloxacin (26/27, 96.3%), ticarcillin (27/27, 100%), ceftazidime (27/27, 100%), doxycycline (25/27, 92.6%)
The TSP-AB-03 strain was treated with 1× minimum inhibitory concentration (MIC) (2 μg/mL) of AS101 and its surface morphological changes, compared to the untreated group, were observed using a scanning electron microscope (SEM) (Figure 3)
Compared to the untreated group (Figure 4a,b), transmission electron microscope (TEM) showed that ghost cells were the most evident structural changes found in AS101-treated bacteria at 12,000× and 20,000× magnification (Figure 4c,d), with the distortion of the cell sizes and shape in the micrograph

Summary

Introduction

Acinetobacter baumannii is a causative organism of nosocomial infections, including pneumonia, sepsis and urinary tract infection, and its propensity to acquire multidrug, extensively drug and pan-drug resistance make it a global threat in healthcare settings [1,2]. Carbapenems were considered as one of the last-line resorts against A. baumannii infections. Due to the increasing consumption of carbapenems, the increasing trend of carbapenem resistance in A. baumannii (CRAB) worldwide has become a concern, limiting therapeutic alternatives and increasing morbidity and mortality rates. Jamie et al reviewed published reports from nosocomial settings in Latin America published between 2002 and 2013 [3]. Rates of carbapenem resistance were found as high as 90% for A. baumannii isolates across Latin America. In a surveillance study in the US, 1490 A. baumannii isolates were collected from healthcare-associated infections during

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