Hệ thống quản lý khoa học - 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

Tên bài báo:	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 (Lượt xem: )
Tên tạp chí:	Frontiers in Microbiology
Tạp chí thuộc:	Tạp chí KH quốc tế ISI
Chỉ số IF/H:	4.235 (Q1*)
Năm xuất bản:	2020
Nước xuất bản:	Thụy Sỹ
Tác giả thuộc Học viện:	ThS Nguyễn Thị Hằng (TY)
Các tác giả bài báo:	Hongfei Pi1†, Hang Thi Nguyen1,2† (đồng tác giả chính), Henrietta Venter3, Alexandra R. Boileau1, Lucy Woolford4, Sanjay Garg5, Stephen W. Page6, Cecilia C. Russell7, Jennifer R. Baker7, Adam McCluskey7, Lisa A. O’Donovan8, Darren J. Trott1* and Abiodun D. Ogunniyi1* 1 Australian Centre for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy, SA, Australia, 2 Department of Pharmacology, Toxicology, Internal Medicine and Diagnostics, Faculty of Veterinary Medicine, Vietnam National University of Agriculture, Hanoi, Vietnam, 3 Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia, 4 School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy, SA, Australia, 5 Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia, 6 Neoculi Pty. Ltd., Burwood, VIC, Australia, 7 Chemistry, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW, Australia, 8 ARC Centre of Excellence in Plant Energy Biology, School of Agriculture, Food & Wine, The University of Adelaide, Urrbrae, SA, Australia
Tóm tắt bài báo:	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 mg/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 Frontiers in 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.
Link:	https://www.frontiersin.org/articles/10.3389/fmicb.2020.01556/full