Morpholino Oligomers Tested in Vitro, in Biofilm and in Vivo Against Multidrug-resistant Klebsiella Pneumoniae

Overview

Journal J Antimicrob Chemother

Publisher Oxford University Press

Specialty Infectious Diseases

Date 2018 Mar 6

PMID 29506074

Citations 16

Authors

Bruce L Geller

Lixin Li

Fabian Martinez

Erin Sully

Carolyn R Sturge

Seth M Daly

Christine Pybus

David E Greenberg

Affiliations

Soon will be listed here.

Abstract

Background: Klebsiella pneumoniae is an opportunistic pathogen and many strains are multidrug resistant. KPC is one of the most problematic resistance mechanisms, as it confers resistance to most β-lactams, including carbapenems. A promising platform technology for treating infections caused by MDR pathogens is the nucleic acid-like synthetic oligomers that silence bacterial gene expression by an antisense mechanism.

Objectives: To test a peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) in a mouse model of K. pneumoniae infection.

Methods: PPMOs were designed to target various essential genes of K. pneumoniae and screened in vitro against a panel of diverse strains. The most potent PPMOs were further tested for their bactericidal effects in broth cultures and in established biofilms. Finally, a PPMO was used to treat mice infected with a KPC-expressing strain.

Results: The most potent PPMOs targeted acpP, rpmB and ftsZ and had MIC75s of 0.5, 4 and 4 μM, respectively. AcpP PPMOs were bactericidal at 1-2 × MIC and reduced viable cells and biofilm mass in established biofilms. In a mouse pneumonia model, therapeutic intranasal treatment with ∼30 mg/kg AcpP PPMO improved survival by 89% and reduced bacterial burden in the lung by ∼3 logs. Survival was proportional to the dose of AcpP PPMO. Delaying treatment by 2, 8 or 24 h post-infection improved survival compared with control groups treated with PBS or scrambled sequence (Scr) PPMOs.

Conclusions: PPMOs have the potential to be effective therapeutic agents against KPC-expressing, MDR K. pneumoniae.

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