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

Pi, Hongfei; Nguyen, HoangKim; Venter, Henrietta; Boileau, Alexandra; 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.

doi:10.3389/fmicb.2020.01556

Cited by 14 publications

(31 citation statements)

References 37 publications

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“…It is known that colistin interacts with the lipopolysaccharide on the surface of Gram-negative bacteria and then across the outer membrane via the self-promoted uptake pathway, resulting in disruption of the normal barrier property of the outer membrane [ 2 , 31 ]. Subsequently, the outer membrane is hypothesized to transiently open thereby allowing passage of NCL195 into the cell to the drug target site(s), likely to be located on the plasma membrane, as we described recently [ 11 ]. Based on this hypothesis, we initially determined the optimal time point of colistin treatment that would result in the disruption of the outer membrane using two growth stages of Xen14 ( A 600nm = 0.1 or A 600nm = 0.5).…”

Section: Resultsmentioning

confidence: 99%

“…The mechanism of beneficial combination treatment is proposed to involve complete integration of polymyxins into the outer membrane causing disorganization and neutralization of cell surface charge and consequently loss of envelope barrier function. Subsequently, the affected outer membrane is hypothesized to transiently open, allowing entry of the second antibiotic and interaction with otherwise inaccessible drug target sites [ 2 , 10 , 11 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

“…Our ongoing studies have indicated potential therapeutic options using the novel pyrimidine NCL195, 4,6-bis(2-(( E )-4-methylbenzylidene)hydrazineyl)pyrimidin-2-amine ( Figure 1 ) combined with subinhibitory concentrations of polymyxin B (PMB) or colistin against Gram-negative infections [ 10 , 11 ]. We showed synergistic activity of the NCL195-PMB or NCL195-colistin combination against clinical Gram-negative bacterial pathogens, with MICs for NCL195 ranging from 0.25–4 µg/mL for Acinetobacter baumannii , Escherichia coli , Klebsiella pneumoniae and Pseudomonas aeruginosa , whereas NCL195 alone had no activity.…”

Section: Introductionmentioning

confidence: 99%

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Comparison of Two Transmission Electron Microscopy Methods to Visualize Drug-Induced Alterations of Gram-Negative Bacterial Morphology

et al. 2021

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In this study, we optimized and compared different transmission electron microscopy (TEM) methods to visualize changes to Gram-negative bacterial morphology induced by treatment with a robenidine analogue (NCL195) and colistin combination. Aldehyde-fixed bacterial cells (untreated, treated with colistin or NCL195 + colistin) were prepared using conventional TEM methods and compared with ultrathin Tokuyasu cryo-sections. The results of this study indicate superiority of ultrathin cryo-sections in visualizing the membrane ultrastructure of Escherichia coli and Pseudomonas aeruginosa, with a clear delineation of the outer and inner membrane as well as the peptidoglycan layer. We suggest that the use of ultrathin cryo-sectioning can be used to better visualize and understand drug interaction mechanisms on the bacterial cell membrane.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comparison of Two Transmission Electron Microscopy Methods to Visualize Drug-Induced Alterations of Gram-Negative Bacterial Morphology

et al. 2021

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“…The minimum inhibitory concentrations (MICs) of benzguinols A and B against MRSP and selected GNB were determined in round bottom 96-well microtiter plates (Sarstedt 82.1582.001; Mawson Lakes, SA, Australia), using the modified broth micro-dilution method according to recommendations by the Clinical and Laboratory Standards Institute [ 29 ] as described previously [ 30 ]. Briefly, antimicrobial challenge plates were prepared by serial two-fold dilutions of stock solutions of benzguinol A or B in DMSO.…”

Section: Methodsmentioning

confidence: 99%

Evaluation of Benzguinols as Next-Generation Antibiotics for the Treatment of Multidrug-Resistant Bacterial Infections

Nguyen

Morshed

Vuong³

et al. 2021

Antibiotics

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Our recent focus on the “lost antibiotic” unguinol and related nidulin-family fungal natural products identified two semisynthetic derivatives, benzguinols A and B, with unexpected in vitro activity against Staphylococcus aureus isolates either susceptible or resistant to methicillin. Here, we show further activity of the benzguinols against methicillin-resistant isolates of the animal pathogen Staphylococcus pseudintermedius, with minimum inhibitory concentration (MIC) ranging 0.5–1 μg/mL. When combined with sub-inhibitory concentrations of colistin, the benzguinols demonstrated synergy against Gram-negative reference strains of Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa (MICs of 1–2 μg/mL in the presence of colistin), whereas the benzguinols alone had no activity. Administration of three intraperitoneal (IP) doses of 20 mg/kg benzguinol A or B to mice did not result in any obvious adverse clinical or pathological evidence of acute toxicity. Importantly, mice that received three 20 mg/kg IP doses of benzguinol A or B at 4 h intervals exhibited significantly reduced bacterial loads and longer survival times than vehicle-only treated mice in a bioluminescent S. aureus murine sepsis challenge model. We conclude that the benzguinols are potential candidates for further development for specific treatment of serious bacterial infections as both stand-alone antibiotics and in combination with existing antibiotic classes.

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“…As such, NCL195 is not suitable for further development, but its scaffold could be used in further research (Pi et al . 2020 ).…”

Section: Introductionmentioning

confidence: 99%

The search for novel treatment strategies forStreptococcus pneumoniaeinfections

Cools

Delputte

Cos

2021

FEMS Microbiology Reviews

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This review provides an overview of the most important novel treatment strategies against Streptococcus pneumoniae infections published over the past 10 years. The pneumococcus causes the majority of community-acquired bacterial pneumonia cases, and it is one of the prime pathogens in bacterial meningitis. Over the last 10 years, extensive research has been conducted to prevent severe pneumococcal infections, with a major focus on (i) boosting the host immune system and (ii) discovering novel antibacterials. Boosting the immune system can be done in two ways, either by actively modulating host immunity, mostly through administration of selective antibodies, or by interfering with pneumococcal virulence factors, thereby supporting the host immune system to effectively overcome an infection. While several of such experimental therapies are promising, few have evolved to clinical trials. The discovery of novel antibacterials is hampered by the high research and development costs versus the relatively low revenues for the pharmaceutical industry. Nevertheless, novel enzymatic assays and target-based drug design, allow the identification of targets and the development of novel molecules to effectively treat this life-threatening pathogen.

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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

Cited by 14 publications

References 37 publications

Comparison of Two Transmission Electron Microscopy Methods to Visualize Drug-Induced Alterations of Gram-Negative Bacterial Morphology

Comparison of Two Transmission Electron Microscopy Methods to Visualize Drug-Induced Alterations of Gram-Negative Bacterial Morphology

Evaluation of Benzguinols as Next-Generation Antibiotics for the Treatment of Multidrug-Resistant Bacterial Infections

The search for novel treatment strategies forStreptococcus pneumoniaeinfections

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