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Type: Journal article
Title: In vitro activity of robenidine Analog NCL195 in combination with outer membrane permeabilizers against gram-negative bacterial pathogens and impact on systemic gram-positive bacterial infection in mice
Author: Pi, H.
Nguyen, H.T.
Venter, H.
Boileau, A.R.
Woolford, L.
Garg, S.
Page, S.W.
Russell, C.C.
Baker, J.R.
McCluskey, A.
O'Donovan, L.A.
Trott, D.J.
Ogunniyi, A.D.
Citation: Front Microbiol, 2020; 11:1556
Publisher: Frontiers
Issue Date: 2020
ISSN: 1664-302X
1664-302X
Statement of
Responsibility: 
Hongfei Pi, Hang Thi Nguyen, Henrietta Venter, Alexandra R. Boileau, Lucy Woolford, Sanjay Garg ... et al.
Abstract: Multidrug-resistant (MDR) pathogens, particularly the ESKAPE group (Enterococcus faecalis/faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, and Enterobacter spp.), have become a public health threat worldwide. Development of new antimicrobial classes and the use of drugs in combination are potential strategies to treat MDR ESKAPE pathogen infections and promote optimal antimicrobial stewardship. Here, the in vitro antimicrobial activity of robenidine analog NCL195 alone or in combination with different concentrations of three outer membrane permeabilizers [ethylenediaminetetraacetic acid (EDTA), polymyxin B nonapeptide (PMBN), and polymyxin B (PMB)] was further evaluated against clinical isolates and reference strains of key Gram-negative bacteria. NCL195 alone was bactericidal against Neisseria meningitidis and Neisseria gonorrhoeae (MIC/MBC = 32 μg/mL) and demonstrated synergistic activity against P. aeruginosa, E. coli, K. pneumoniae, and Enterobacter spp. strains in the presence of subinhibitory concentrations of EDTA, PMBN, or PMB. The additive and/or synergistic effects of NCL195 in combination with EDTA, PMBN, or PMB are promising developments for a new chemical class scaffold to treat Gram-negative infections. Tokuyasu cryo ultramicrotomy was used to visualize the effect of NCL195 on bioluminescent S. aureus membrane morphology. Additionally, NCL195's favorable pharmacokinetic and pharmacodynamic profile was further explored in in vivo safety studies in mice and preliminary efficacy studies against Gram-positive bacteria. Mice administered two doses of NCL195 (50 mg/kg) by the intraperitoneal (IP) route 4 h apart showed no adverse clinical effects and no observable histological effects in major organs. In bioluminescent Streptococcus pneumoniae and S. aureus murine sepsis challenge models, mice that received two 50 mg/kg doses of NCL195 4 or 6 h apart exhibited significantly reduced bacterial loads and longer survival times than untreated mice. However, further medicinal chemistry and pharmaceutical development to improve potency, solubility, and selectivity is required before efficacy testing in Gram-negative infection models.
Keywords: Bacterial sepsis; bioluminescence; cryo-ultramicrotomy; membrane potential; multidrug resistance; NCL195; polymyxin B; transmission electron microscopy
Rights: © 2020 Pi, Nguyen, Venter, Boileau, Woolford, Garg, Page, Russell, Baker, McCluskey, O’Donovan, Trott and Ogunniyi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
RMID: 1000025270
DOI: 10.3389/fmicb.2020.01556
Grant ID: http://purl.org/au-research/grants/arc/LP110200770
Appears in Collections:Microbiology and Immunology publications

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