In Vitro Activity of a Novel Siderophore-Cephalosporin, GT-1 and Serine-Type β-Lactamase Inhibitor, GT-055, against Escherichia coli, Klebsiella pneumoniae and Acinetobacter spp. Panel Strains.

Le Phuong Nguyen,Young Lag Cho,Thao Nguyen Vu,Hyunsook Lee,Roshan D’Souza,Naina Adren Pinto,Jung-Hyun Byun,Dongeun Yong

doi:10.3390/antibiotics9050267

Abstract

This study investigates GT-1 (also known as LCB10-0200), a novel-siderophore cephalosporin, inhibited multidrug-resistant (MDR) Gram-negative pathogen, via a Trojan horse strategy exploiting iron-uptake systems. We investigated GT-1 activity and the role of siderophore uptake systems, and the combination of GT-1 and a non-β-lactam β-lactamase inhibitor (BLI) of diazabicyclooctane, GT-055, (also referred to as LCB18-055) against molecularly characterised resistant Escherichia coli, Klebsiella pneumoniae and Acinetobacter spp. isolates. GT-1 and GT-1/GT-055 were tested in vitro against comparators among three different characterised panel strain sets. Bacterial resistome and siderophore uptake systems were characterised to elucidate the genetic basis for GT-1 minimum inhibitory concentrations (MICs). GT-1 exhibited in vitro activity (≤2 μg/mL MICs) against many MDR isolates, including extended-spectrum β-lactamase (ESBL)- and carbapenemase-producing E. coli and K. pneumoniae and oxacillinase (OXA)-producing Acinetobacter spp. GT-1 also inhibited strains with mutated siderophore transporters and porins. Although BLI GT-055 exhibited intrinsic activity (MIC 2–8 μg/mL) against most E. coli and K. pneumoniae isolates, GT-055 enhanced the activity of GT-1 against many GT-1–resistant strains. Compared with CAZ-AVI, GT-1/GT-055 exhibited lower MICs against E. coli and K. pneumoniae isolates. GT-1 demonstrated potent in vitro activity against clinical panel strains of E. coli, K. pneumoniae and Acinetobacter spp. GT-055 enhanced the in vitro activity of GT-1 against many GT-1–resistant strains.

Highlights

The World Health Organisation has prioritised third-generation cephalosporin and carbapenem-resistant Enterobacteriaceae and Acinetobacter baumannii as critical pathogens for research and development of new antibiotic drugs [1]
The β-lactamase producers present in these diverse specimens included strains producing non-extended-spectrum β-lactamase (ESBLs) (TEM-1B, TEM-1C, SHV-11, OXA-1, OXA-10), ESBLs (CTX-M-14, CTX-M-15, CTX-M-27, CTX-M-55, CTX-M-65), AmpC (ACT-2, CMY-2) and carbapenemases (KPC-2, OXA-48) (Table 1)
The GT-1 minimum inhibitory concentrations (MICs) ranged from ≤0.12 to 1 μg/mL against E. coli MDR isolates producing KPCor OXA-carbapenemases, ESBLs CTX-M-14 or CTX-M-55 and CMY-2 AmpC β-lactamase

Summary

Introduction

The World Health Organisation has prioritised third-generation cephalosporin and carbapenem-resistant Enterobacteriaceae and Acinetobacter baumannii as critical pathogens for research and development of new antibiotic drugs [1]. Antibiotics 2020, 9, 267; doi:10.3390/antibiotics9050267 www.mdpi.com/journal/antibiotics have made treatment more challenging [2,3] This has highlighted the importance of developing new antibiotics to address the problem of antibiotic resistance. Of in developing contrast to new the rapid and treatment more challenging [2,3]. This has highlighted the importance antibiotics continuous escalation in of theantibiotic emergence of multidrug-resistant (MDR) Gram-negative and to address the problem resistance. In contrast to the rapid andbacteria continuous the diminishing of the current antibiotic arsenal, there has been bacteria a lag in and investment in new escalation in the efficacy emergence of multidrug-resistant (MDR) Gram-negative the diminishing research and development [1]. A bottleneck in current designing novel efficacy of thedrug current antibiotic arsenal, there has been a lag inapproaches investment for in new research and antibiotics is the limited of drug as components of nucleic acid synthesisisand drug development [1]. number

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Conclusion