In Vitro Activity of Robenidine Analogues NCL259 and NCL265 against Gram-Negative Pathogens.

Multidrug-resistant (MDR) Gram-negative pathogens, especially Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli and Enterobacter spp., are recognized by the World Health Organization as the most critical priority pathogens in urgent need of drug development. In this study, the in vitro antimicrobial activity of robenidine analogues NCL259 and NCL265 was tested against key human and animal Gram-negative clinical isolates and reference strains.

Repurposing of the Fasciolicide Triclabendazole to Treat Infections Caused by spp. and Vancomycin-Resistant Enterococci.

One approach to combat the increasing incidence of multidrug-resistant (MDR) bacterial pathogens involves repurposing existing compounds with known safety and development pathways as new antibacterial classes with potentially novel mechanisms of action. Here, triclabendazole (TCBZ), a drug originally developed to treat (liver fluke) in sheep and cattle, and later in humans, was evaluated as an antibacterial alone or in combination with sub-inhibitory concentrations of polymyxin B (PMB) against clinical isolates and reference strains of key Gram-positive and Gram-negative bacteria. We show for the first time that in vitro, TCBZ selectively kills methicillin-sensitive and methicillin-resistant and at a minimum inhibitory concentration (MIC) range of 2-4 µg/mL, and vancomycin-resistant enterococci at a MIC range of 4-8 µg/mL.

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

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 isolates either susceptible or resistant to methicillin. Here, we show further activity of the benzguinols against methicillin-resistant isolates of the animal pathogen , with minimum inhibitory concentration (MIC) ranging 0.5-1 μg/mL.

A pH-neutral electrolyzed oxidizing water significantly reduces microbial contamination of fresh spinach leaves.

There are growing demands globally to use safe, efficacious and environmentally friendly sanitizers for post-harvest treatment of fresh produce to reduce or eliminate spoilage and foodborne pathogens. Here, we compared the efficacy of a pH-neutral electrolyzed oxidizing water (Ecas4 Anolyte; ECAS) with that of an approved peroxyacetic acid-based sanitizer (Ecolab Tsunami® 100) in reducing the total microbial load and inoculated Escherichia coli, Salmonella Enteritidis and Listeria innocua populations on post-harvest baby spinach leaves over 10 days. The impact of both sanitizers on the overall quality of the spinach leaves during storage was also assessed by shelf life and vitamin C content measurements.

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.

Multidrug-resistant (MDR) pathogens, particularly the ESKAPE group (, , , , , , and 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.

Discovery of 4,6-bis(2-(()-benzylidene)hydrazinyl)pyrimidin-2-Amine with Antibiotic Activity.

Robenidine ()-'-(()-1-(4-chlorophenyl)ethylidene)-2-(1-(4-chlorophenyl)ethylidene)hydrazine-1-carboximidhydrazide displays methicillin-resistant (MRSA) and vancomycin-resistant Enterococci (VRE) MICs of 2 μg mL. Herein we describe the structure-activity relationship development of a novel series of guanidine to 2-aminopyrimidine isosteres that ameliorate the low levels of mammalian cytotoxicity in the lead compound while retaining good antibiotic activity. Removal of the 2-NH pyrimidine moiety renders these analogues inactive.

Antimicrobial Activity of Robenidine, Ethylenediaminetetraacetic Acid and Polymyxin B Nonapeptide Against Important Human and Veterinary Pathogens.

The emergence and global spread of antimicrobial resistance among bacterial pathogens demand alternative strategies to treat life-threatening infections. Combination drugs and repurposing of old compounds with known safety profiles that are not currently used in human medicine can address the problem of multidrug-resistant infections and promote antimicrobial stewardship in veterinary medicine. In this study, the antimicrobial activity of robenidine alone or in combination with ethylenediaminetetraacetic acid (EDTA) or polymyxin B nonapeptide (PMBN) against Gram-negative bacterial pathogens, including those associated with canine otitis externa and human skin and soft tissue infection, was evaluated using microdilution susceptibility testing and the checkerboard method.

Gram-Positive and Gram-Negative Antibiotic Activity of Asymmetric and Monomeric Robenidine Analogues.

Desymmetrisation of robenidine (1: N',2-bis((E)-4-chlorobenzylidene)hydrazine-1-carboximidhydrazide) and the introduction of imine alkyl substituents gave good antibiotic activity. Of note was the increased potency of two analogues against vancomycin-resistant Enterococci (VRE), one of which returned a MIC of 0.5 μg mL .

Evaluation of robenidine analog NCL195 as a novel broad-spectrum antibacterial agent.

The spread of multidrug resistance among bacterial pathogens poses a serious threat to public health worldwide. Recent approaches towards combating antimicrobial resistance include repurposing old compounds with known safety and development pathways as new antibacterial classes with novel mechanisms of action. Here we show that an analog of the anticoccidial drug robenidine (4,6-bis(2-((E)-4-methylbenzylidene)hydrazinyl)pyrimidin-2-amine; NCL195) displays potent bactericidal activity against Streptococcus pneumoniae and Staphylococcus aureus by disrupting the cell membrane potential.

Efficacy evaluation of a new water sanitizer for increasing the shelf life of Southern Australian King George Whiting and Tasmanian Atlantic Salmon fillets.

The bacterial species and specific spoilage organisms associated with the Southern Australian King George Whiting (KGW) and Tasmanian Atlantic Salmon (TAS), and the efficacy of a HOCl-containing water-based sanitization product (Electro-Chemically Activated Solution, by ECAS4) in extending the shelf life of KGW and TAS fillets were evaluated. Fillets were washed with an ECAS4 solution containing either 45 ppm or 150 ppm of free chlorine and bacterial species enumerated on selective and non-selective media, followed by identification of pure isolates by 16 S rRNA gene sequencing. The dominant spoilage microbiota in KGW and TAS fillets stored at 4 ± 1 °C were Pseudomonas spp.

Genetic Structure and Antimicrobial Resistance of Escherichia coli and Cryptic Clades in Birds with Diverse Human Associations.

The manner and extent to which birds associate with humans may influence the genetic attributes and antimicrobial resistance of their commensal Escherichia communities through strain transmission and altered selection pressures. In this study, we determined whether the distribution of the different Escherichia coli phylogenetic groups and cryptic clades, the occurrence of 49 virulence associated genes, and/or the prevalence of resistance to 12 antimicrobials differed between four groups of birds from Australia with contrasting types of human association. We found that birds sampled in suburban and wilderness areas had similar Escherichia communities.