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
| Autor: | Abiodun D. Ogunniyi, Darren J. Trott, Lisa A. O’Donovan, Henrietta Venter, Jennifer R. Baker, Lucy Woolford, Stephen W. Page, Cecilia C. Russell, Hongfei Pi, Hang Thi Nguyen, Adam McCluskey, Alexandra R Boileau, Sanjay Garg |
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| Přispěvatelé: | Pi, Hongfei, Nguyen, Hang Thi, Venter, Henrietta, Boileau, Alexandra R, Woolford, Lucy, Garg, Sanjay, Page, Stephen W, Russell, Cecilia C, Baker, Jennifer R, McCluskey, Adam, O'Donovan, Lisa A, Trott, Darren J, Ogunniyi, Abiodun D |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Microbiology (medical)
bacterial sepsis lcsh:QR1-502 medicine.disease_cause Microbiology Enterococcus faecalis lcsh:Microbiology 03 medical and health sciences multidrug resistance transmission electron microscopy medicine cryo-ultramicrotomy 030304 developmental biology Original Research 0303 health sciences biology 030306 microbiology Pseudomonas aeruginosa Chemistry polymyxin B Enterobacter biology.organism_classification Antimicrobial bioluminescence Acinetobacter baumannii Multiple drug resistance Staphylococcus aureus membrane potential NCL195 Polymyxin B medicine.drug |
| Zdroj: | Frontiers in Microbiology Frontiers in Microbiology, Vol 11 (2020) |
| ISSN: | 1664-302X |
| Popis: | usc 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. Refereed/Peer-reviewed |
| Databáze: | OpenAIRE |
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