35 results on '"Page, Stephen W."'
Search Results
2. Antimicrobial stewardship: a definition with a One Health perspective
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Hibbard, Rebecca, Mendelson, Marc, Page, Stephen W., Ferreira, Jorge Pinto, Pulcini, Céline, Paul, Mathilde C., and Faverjon, Céline
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- 2024
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3. Oral administration of a 2-aminopyrimidine robenidine analogue (NCL195) significantly reduces Staphylococcus aureus infection and reduces Escherichia coli infection in combination with sub-inhibitory colistin concentrations in a bioluminescent mouse model
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Nguyen, Hang Thi, primary, Venter, Henrietta, additional, Woolford, Lucy, additional, Young, Kelly A., additional, McCluskey, Adam, additional, Garg, Sanjay, additional, Sapula, Sylvia S., additional, Page, Stephen W., additional, Ogunniyi, Abiodun David, additional, and Trott, Darren J., additional
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- 2023
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4. Aminoguanidines: New leads for treatment of Giardia duodenalis infection
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Abraham, Rebecca J., Abraham, Sam, Stevens, Andrew J., Page, Stephen W., McCluskey, Adam, Trott, Darren J., and O'Handley, Ryan M.
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- 2019
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5. Advanced Strategies of Drug Delivery via Oral, Topical, and Parenteral Administration Routes: Where Do Equine Medications Stand?
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Song, Yunmei, primary, Day, Candace M., additional, Afinjuomo, Franklin, additional, Tan, Jin-Quan E., additional, Page, Stephen W., additional, and Garg, Sanjay, additional
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- 2023
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6. In Vitro Activity of Robenidine Analogues NCL259 and NCL265 against Gram-Negative Pathogens
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Pi, Hongfei, primary, Venter, Henrietta, additional, Russell, Cecilia C., additional, Young, Kelly A., additional, McCluskey, Adam, additional, Page, Stephen W., additional, Ogunniyi, Abiodun D., additional, and Trott, Darren J., additional
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- 2022
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7. Impact of a Novel Anticoccidial Analogue on Systemic Staphylococcus aureus Infection in a Bioluminescent Mouse Model
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Nguyen, Hang Thi, primary, Venter, Henrietta, additional, Woolford, Lucy, additional, Young, Kelly, additional, McCluskey, Adam, additional, Garg, Sanjay, additional, Page, Stephen W., additional, Trott, Darren J., additional, and Ogunniyi, Abiodun David, additional
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- 2022
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8. Repurposing of the Fasciolicide Triclabendazole to Treat Infections Caused by Staphylococcus spp. and Vancomycin-Resistant Enterococci
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Pi, Hongfei, primary, Ogunniyi, Abiodun D., additional, Savaliya, Bhumi, additional, Nguyen, Hang Thi, additional, Page, Stephen W., additional, Lacey, Ernest, additional, Venter, Henrietta, additional, and Trott, Darren J., additional
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- 2021
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9. Comparison of Two Transmission Electron Microscopy Methods to Visualize Drug-Induced Alterations of Gram-Negative Bacterial Morphology
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Nguyen, Hang Thi, primary, O’Donovan, Lisa A., additional, Venter, Henrietta, additional, Russell, Cecilia C., additional, McCluskey, Adam, additional, Page, Stephen W., additional, Trott, Darren J., additional, and Ogunniyi, Abiodun D., additional
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- 2021
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10. 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
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Pi, Hongfei, primary, Nguyen, Hang Thi, additional, Venter, Henrietta, additional, Boileau, Alexandra R., additional, Woolford, Lucy, additional, Garg, Sanjay, additional, Page, Stephen W., additional, Russell, Cecilia C., additional, Baker, Jennifer R., additional, McCluskey, Adam, additional, O’Donovan, Lisa A., additional, Trott, Darren J., additional, and Ogunniyi, Abiodun D., additional
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- 2020
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11. Discovery of 4,6‐bis(2‐(( E )‐benzylidene)hydrazinyl)pyrimidin‐2‐Amine with Antibiotic Activity
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Russell, Cecilia C., primary, Stevens, Andrew, additional, Young, Kelly A., additional, Baker, Jennifer R., additional, McCluskey, Siobhann N., additional, Khazandi, Manouchehr, additional, Pi, Hongfei, additional, Ogunniyi, Abiodun, additional, Page, Stephen W., additional, Trott, Darren J., additional, and McCluskey, Adam, additional
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- 2019
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12. In vitro Antimicrobial Activity of Robenidine, Ethylenediaminetetraacetic Acid and Polymyxin B Nonapeptide Against Important Human and Veterinary Pathogens
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Khazandi, Manouchehr, primary, Pi, Hongfei, additional, Chan, Wei Yee, additional, Ogunniyi, Abiodun David, additional, Sim, Jowenna Xiao Feng, additional, Venter, Henrietta, additional, Garg, Sanjay, additional, Page, Stephen W., additional, Hill, Peter B., additional, McCluskey, Adam, additional, and Trott, Darren J., additional
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- 2019
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13. Bioluminescent murine models of bacterial sepsis and scald wound infections for antimicrobial efficacy testing
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Ogunniyi, Abiodun D., primary, Kopecki, Zlatko, additional, Hickey, Elizabeth E., additional, Khazandi, Manouchehr, additional, Peel, Emma, additional, Belov, Katherine, additional, Boileau, Alexandra, additional, Garg, Sanjay, additional, Venter, Henrietta, additional, Chan, Wei Yee, additional, Hill, Peter B., additional, Page, Stephen W., additional, Cowin, Allison J., additional, and Trott, Darren J., additional
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- 2018
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14. Antimicrobial Stewardship in Veterinary Medicine
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Lloyd, David H., primary and Page, Stephen W., additional
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- 2018
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15. Evaluation of robenidine analog NCL195 as a novel broad-spectrum antibacterial agent
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Ogunniyi, Abiodun D., primary, Khazandi, Manouchehr, additional, Stevens, Andrew J., additional, Sims, Sarah K., additional, Page, Stephen W., additional, Garg, Sanjay, additional, Venter, Henrietta, additional, Powell, Andrew, additional, White, Karen, additional, Petrovski, Kiro R., additional, Laven-Law, Geraldine, additional, Tótoli, Eliane G., additional, Salgado, Hérida R., additional, Pi, Hongfei, additional, Coombs, Geoffrey W., additional, Shinabarger, Dean L., additional, Turnidge, John D., additional, Paton, James C., additional, McCluskey, Adam, additional, and Trott, Darren J., additional
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- 2017
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16. Feline Focus
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Malik, Richard, primary, Fawcett, Anne, additional, Page, Stephen W, additional, Seavers, Aine, additional, Campbell, Alex, additional, Sutton, Nick, additional, Sparkes, Andy, additional, Tiffin, Ross, additional, and Bessant, Claire, additional
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- 2011
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17. Development of intramammary delivery systems containing lasalocid for the treatment of bovine mastitis: impact of solubility improvement on safety, efficacy, and milk distribution in dairy cattle.
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Wen Wang, Yunmei Song, Kiro Petrovski, Eats, Patricia, Trott, Darren J., Hui San Wong, Page, Stephen W., Perry, Jeanette, and Garg, Sanjay
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- 2015
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18. Evaluation of Benzguinols as Next-Generation Antibiotics for the Treatment of Multidrug-Resistant Bacterial Infections.
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Nguyen, Hang Thi, Morshed, Mahmud T., Vuong, Daniel, Crombie, Andrew, Lacey, Ernest, Garg, Sanjay, Pi, Hongfei, Woolford, Lucy, Venter, Henrietta, Page, Stephen W., Piggott, Andrew M., Trott, Darren J., and Ogunniyi, Abiodun D.
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BACTERIAL diseases ,ANTIBIOTICS ,ACINETOBACTER baumannii ,COLISTIN ,STAPHYLOCOCCUS aureus - Abstract
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. [ABSTRACT FROM AUTHOR]
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- 2021
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19. Physicochemical properties of otic products for Canine Otitis Externa: comparative analysis of marketed products
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Yunmei Song, Sadikalmahdi Abdella, Franklin Afinjuomo, Emily Josephine Weir, Jin Quan Eugene Tan, Peter Hill, Stephen W. Page, Sanjay Garg, Song, Yunmei, Abdella, Sadikalmahdi, Afinjuomo, Franklin, Weir, Emily Josephine, Tan, Jin Quan Eugene, Hill, Peter, Page, Stephen W, and Garg, Sanjay
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formulation development ,General Veterinary ,physicochemical properties ,General Medicine ,canine otitis externa - Abstract
Background Otitis externa is a commonly diagnosed dermatological disorder in canines. The pathogens primarily involved in canine otitis externa (COE) include Staphylococcus pseudintermedius, Pseudomonas aeruginosa, Proteus mirabilis, and Malassezia pachydermatis. As COE tends to be superficial, medications delivered topically are often effective and practical in managing the condition. As such, there is a wide variety of approved topical products currently available in the market. The efficacy of topical dosage forms can be dependent on various factors such as the pharmacology of active constituents and the physicochemical properties of the formulation, including pH, viscosity, spreadability, and bio-adhesion. Currently, there is a lack of published literature available on the optimal properties of topical COE products. In this study, we compared the physicochemical properties of nine commercially available otic veterinarian products in Australia used clinically to manage COE. Results Based on our comparative analysis, the pH (6.26 ± 0.04) of an aqueous-based product was similar to a healthy dog’s external auditory canal. Products containing polymers exhibited higher viscosity and bio-adhesion. Spreadability was inversely related to viscosity and Osurnia ® a product with high viscosity demonstrated the lowest spreadability. Aqueous-based otic products showed better syringebility whereas oil-based systems required higher force to expel the products. Variability in droplet size was noted. Derm Otic, Baytril Otic, and Aurizon Ear Drops had the lower standard deviation which indicates they would give a more consistent dose. Conclusions Findings from this work provide considerations for industry researchers or formulation scientists working in the area of otic dosage formulations.
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- 2023
20. Advanced Strategies of Drug Delivery via Oral, Topical, and Parenteral Administration Routes: Where Do Equine Medications Stand?
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Yunmei Song, Candace M. Day, Franklin Afinjuomo, Jin-Quan E. Tan, Stephen W. Page, Sanjay Garg, Song, Yunmei, Day, Candace M, Afinjuomo, Franklin, Tan, Jin Quan E, Page, Stephen W, and Garg, Sanjay
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oral ,injection ,Pharmaceutical Science ,topical ,NDDSs ,equine - Abstract
Refereed/Peer-reviewed While the global market for veterinary products has been expanding rapidly, there is still a lack of specialist knowledge of equine pharmaceutics. In many cases, the basic structure of the gastrointestinal tract (GIT) and integumentary system of the horse shares similarities with those of humans. Generally, the dosage form developed for humans can be repurposed to deliver equine medications; however, due to physiological variation, the therapeutic outcomes can be unpredictable. This is an area that requires more research, as there is a clear deficiency in literature precedence on drug delivery specifically for horses. Through a careful evaluation of equine anatomy and physiology, novel drug delivery systems (NDDSs) can be developed to adequately address many of the medical ailments of the horse. In addition to this, there are key considerations when delivering oral, topical, and parenteral drugs to horses, deriving from age and species variation. More importantly, NDDSs can enhance the duration of action of active drugs in animals, significantly improving owner compliance; and ultimately, enhancing the convenience of product administration. To address the knowledge gap in equine pharmaceutical formulations, this paper begins with a summary of the anatomy and physiology of the equine gastrointestinal, integumentary, and circulatory systems. A detailed discussion of potential dosage-form related issues affecting horses, and how they can be overcome by employing NDDSs is presented.
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- 2023
21. Impact of a Novel Anticoccidial Analogue on Systemic Staphylococcus aureus Infection in a Bioluminescent Mouse Model
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Hang Thi Nguyen, Henrietta Venter, Lucy Woolford, Kelly Young, Adam McCluskey, Sanjay Garg, Stephen W. Page, Darren J. Trott, Abiodun David Ogunniyi, Nguyen, Hang Thi, Venter, Henrietta, Woolford, Lucy, Young, Kelly, McCluskey, Adam, Garg, Sanjay, Page, Stephen W., Trott, Darren J, and Ogunniyi, Abiodun David
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Microbiology (medical) ,Staphylococcus aureus ,NCL179 ,antibiotic combination ,RM1-950 ,Gram-positive bacteria ,multidrug-resistance ,bioluminescence ,Biochemistry ,Microbiology ,colistin ,robenidine ,Gram-negative bacteria ,Infectious Diseases ,Pharmacology (medical) ,Therapeutics. Pharmacology ,General Pharmacology, Toxicology and Pharmaceutics - Abstract
In this study, we investigated the potential of an analogue of robenidine (NCL179) to expand its chemical diversity for the treatment of multidrug-resistant (MDR) bacterial infections. We show that NCL179 exhibits potent bactericidal activity, returning minimum inhibitory concentration/minimum bactericidal concentrations (MICs/MBCs) of 1–2 µg/mL against methicillin-resistant Staphylococcus aureus, MICs/MBCs of 1–2 µg/mL against methicillin-resistant S. pseudintermedius and MICs/MBCs of 2–4 µg/mL against vancomycin-resistant enterococci. NCL179 showed synergistic activity against clinical isolates and reference strains of Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa in the presence of sub-inhibitory concentrations of colistin, whereas NCL179 alone had no activity. Mice given oral NCL179 at 10 mg/kg and 50 mg/kg (4 × doses, 4 h apart) showed no adverse clinical effects and no observable histological effects in any of the organs examined. In a bioluminescent S. aureus sepsis challenge model, mice that received four oral doses of NCL179 at 50 mg/kg at 4 h intervals exhibited significantly reduced bacterial loads, longer survival times and higher overall survival rates than the vehicle-only treated mice. These results support NCL179 as a valid candidate for further development to treat MDR bacterial infections as a stand-alone antibiotic or in combination with existing antibiotic classes.
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- 2022
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22. In vitro activity of robenidine analogues NCL259 and NCL265 against Gram-negative pathogens
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Hongfei Pi, Henrietta Venter, Cecilia C. Russell, Kelly A. Young, Adam McCluskey, Stephen W. Page, Abiodun D. Ogunniyi, Darren J. Trott, Pi, Hongfei, Venter, Henrietta, Russell, Cecilia C, Young, Kelly A, McCluskey, Adam, Page, Stephen W, Ogunniyi, Abiodun D, and Trott, Darren J
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Microbiology (medical) ,phenylalanine-arginine-beta-naphthylamide ,Gram-negative pathogens ,efflux pumps ,NCL265 ,polymyxin B ,minimum inhibitory concentration ,NCL259 ,Biochemistry ,Microbiology ,Infectious Diseases ,multidrug resistance ,Pharmacology (medical) ,General Pharmacology, Toxicology and Pharmaceutics - Abstract
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. NCL259 and NCL265 demonstrated moderate antimicrobial activity against these Gram-negative priority pathogens with NCL265 consistently more active, achieving lower minimum inhibitory concentrations (MICs) in the range of 2–16 µg/mL. When used in combination with sub-inhibitory concentrations of polymyxin B to permeabilize the outer membrane, NCL259 and NCL265 elicited a synergistic or additive activity against the reference strains tested, reducing the MIC of NCL259 by 8- to 256- fold and the MIC of NCL265 by 4- to 256- fold. A small minority of Klebsiella spp. isolates (three) were resistant to both NCL259 and NCL265 with MICs > 256 µg/mL. This resistance was completely reversed in the presence of the efflux pump inhibitor phenylalanine-arginine-beta-naphthylamide (PAβN) to yield MIC values of 8–16 µg/mL and 2–4 µg/mL for NCL259 and NCL256, respectively. When NCL259 and NCL265 were tested against wild-type E. coli isolate BW 25113 and its isogenic multidrug efflux pump subunit AcrB deletion mutant (∆AcrB), the MIC of both compounds against the mutant ∆AcrB isolate was reduced 16-fold compared to the wild-type parent, indicating a significant role for the AcrAB-TolC efflux pump from Enterobacterales in imparting resistance to these robenidine analogues. In vitro cytotoxicity testing revealed that NCL259 and NCL265 had much higher levels of toxicity to a range of human cell lines compared to the parent robenidine, thus precluding their further development as novel antibiotics against Gram-negative pathogens.
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- 2022
23. Repurposing of the Fasciolicide Triclabendazole to Treat Infections Caused by Staphylococcus spp. and Vancomycin-Resistant Enterococci
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Henrietta Venter, Ernest Lacey, Hongfei Pi, Stephen W. Page, Darren J. Trott, Abiodun D. Ogunniyi, Hang Thi Nguyen, Bhumi Savaliya, Pi, Hongfei, Ogunniyi, Abiodun D, Savaliya, Bhumi, Nguyen, Hang Thi, Page, Stephen W, Lacey, Ernest, Venter, Henrietta, and Trott, Darren J
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Microbiology (medical) ,Staphylococcus pseudintermedius ,QH301-705.5 ,Biology ,medicine.disease_cause ,Microbiology ,sepsis ,03 medical and health sciences ,Minimum inhibitory concentration ,multidrug resistance ,Virology ,bacterial pathogens ,medicine ,Biology (General) ,030304 developmental biology ,0303 health sciences ,030306 microbiology ,polymyxin B ,triclabendazole ,biology.organism_classification ,bioluminescence ,3. Good health ,Acinetobacter baumannii ,Multiple drug resistance ,Triclabendazole ,Staphylococcus aureus ,Staphylococcus ,Polymyxin B ,medicine.drug - Abstract
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 Fasciola hepatica (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 Staphylococcus aureus and Staphylococcus pseudintermedius 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. TCBZ also inhibited key Gram-negative bacteria in the presence of sub-inhibitory concentrations of PMB, returning MIC90 values of 1 µg/mL for Escherichia coli, 8 µg/mL for Klebsiella pneumoniae, 2 µg/mL for Acinetobacter baumannii and 4 µg/mL for Pseudomonasaeruginosa. Interestingly, TCBZ was found to be bacteriostatic against intracellular S. aureus but bactericidal against intracellular S. pseudintermedius. Additionally, TCBZ’s favourable pharmacokinetic (PK) and pharmacodynamic (PD) profile was further explored by in vivo safety and efficacy studies using a bioluminescent mouse model of S. aureus sepsis. We show that repeated four-hourly oral treatment of mice with 50 mg/kg TCBZ after systemic S. aureus challenge resulted in a significant reduction in S. aureus populations in the blood to 18 h post-infection (compared to untreated mice) but did not clear the bacterial infection from the bloodstream, consistent with in vivo bacteriostatic activity. These results indicate that additional pharmaceutical development of TCBZ may enhance its PK/PD, allowing it to be an appropriate candidate for the treatment of serious MDR bacterial pathogens.
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- 2021
24. Evaluation of Benzguinols as Next-Generation Antibiotics for the Treatment of Multidrug-Resistant Bacterial Infections
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Sanjay Garg, Andrew Crombie, Stephen W. Page, Henrietta Venter, Darren J. Trott, Hang Thi Nguyen, Andrew M. Piggott, Abiodun D. Ogunniyi, Daniel Vuong, Mahmud T. Morshed, Hongfei Pi, Ernest Lacey, Lucy Woolford, Nguyen, Hang Thi, Morshed, Mahmud T, Vuong, Daniel, Crombie, Andrew, Lacey, Ernest, Garg, Sanjay, Pi, Hongfei, Woolford, Lucy, Venter, Henrietta, Page, Stephen W, Piggott, Andrew M, Trott, Darren J, and Ogunniyi, Abiodun D
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0301 basic medicine ,Microbiology (medical) ,Staphylococcus aureus ,Staphylococcus pseudintermedius ,medicine.drug_class ,030106 microbiology ,Antibiotics ,RM1-950 ,minimum inhibitory concentration ,medicine.disease_cause ,Biochemistry ,Microbiology ,Article ,03 medical and health sciences ,Minimum inhibitory concentration ,Antibiotic resistance ,gramnegative ,medicine ,Pharmacology (medical) ,colistin ,antimicrobial resistance ,General Pharmacology, Toxicology and Pharmaceutics ,benzguinols ,biology ,Pseudomonas aeruginosa ,biology.organism_classification ,Gram-negative ,Acinetobacter baumannii ,030104 developmental biology ,Infectious Diseases ,Colistin ,cytotoxicity ,Therapeutics. Pharmacology ,bioluminescent mouse model ,minimuminhibitory concentration ,medicine.drug ,nidulins - Abstract
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.
- Published
- 2021
25. Comparison of Two Transmission Electron Microscopy Methods to Visualize Drug-Induced Alterations of Gram-Negative Bacterial Morphology
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Cecilia C. Russell, Abiodun D. Ogunniyi, Hang Thi Nguyen, Henrietta Venter, Darren J. Trott, Adam McCluskey, Stephen W. Page, Lisa A. O’Donovan, Nguyen, Hang Thi, O'donovan, Lisa A, Venter, Henrietta, Russell, Cecilia C, McCluskey, Adam, Page, Stephen W, Trott, Darren J, and Ogunniyi, Abiodun D
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0301 basic medicine ,Microbiology (medical) ,Gram-negative bacteria ,030106 microbiology ,macromolecular substances ,Biochemistry ,Microbiology ,Article ,Bacterial cell structure ,03 medical and health sciences ,chemistry.chemical_compound ,transmission electron microscopy ,medicine ,Pharmacology (medical) ,colistin ,General Pharmacology, Toxicology and Pharmaceutics ,drug interaction ,biology ,lcsh:RM1-950 ,tokuyasu cryo-ultramicrotomy ,Tokuyasu cryo-ultramicrotomy ,biology.organism_classification ,gram-negative bacteria ,lcsh:Therapeutics. Pharmacology ,030104 developmental biology ,Infectious Diseases ,Membrane ,chemistry ,Transmission electron microscopy ,Colistin ,Ultrastructure ,Biophysics ,bacterial membrane ,Peptidoglycan ,Bacterial cellular morphologies ,medicine.drug ,bacterial cell wall - Abstract
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. Refereed/Peer-reviewed
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- 2021
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26. Gram‐Positive and Gram‐Negative Antibiotic Activity of Asymmetric and Monomeric Robenidine Analogues
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Hongfei Pi, Abiodun D. Ogunniyi, Cecilia C. Russell, Jennifer R. Baker, Adam McCluskey, Manouchehr Khazandi, Andrew Stevens, Siobhann N. McCluskey, Darren J. Trott, Kelly A. Young, Stephen W. Page, Russell, Cecilia C, Stevens, Andrew, Pi, Hongfei, Khazandi, Manouchehr, Ogunniyi, Abiodun D, Young, Kelly A, Baker, Jennifer R, McCluskey, Siobhann N, Page, Stephen W, Trott, Darren J, and McCluskey, Adam
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Methicillin-Resistant Staphylococcus aureus ,0301 basic medicine ,Robenidine ,VRE ,medicine.drug_class ,Stereochemistry ,030106 microbiology ,Antibiotics ,Imine ,Chemistry, Medicinal ,Microbial Sensitivity Tests ,MRSA ,Gram-Positive Bacteria ,Hydrazide ,Biochemistry ,antibiotics ,robenidine ,03 medical and health sciences ,chemistry.chemical_compound ,Gram-Negative Bacteria ,Drug Discovery ,Escherichia coli ,medicine ,Humans ,Moiety ,Potency ,Pharmacology & Pharmacy ,General Pharmacology, Toxicology and Pharmaceutics ,Pharmacology ,Indole test ,drug repurposing ,Organic Chemistry ,Bacterial Infections ,Anti-Bacterial Agents ,3. Good health ,030104 developmental biology ,Monomer ,chemistry ,Drug Design ,Pseudomonas aeruginosa ,Molecular Medicine - Abstract
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 mu g mL(-1). Five analogues were found to be equipotent or more potent than the lead 1. Introduction of an indole moiety resulted in the most active robenidine analogue against methicillin-resistant S. aureus (MRSA), with a MIC of 1.0 mu g mL(-1). Imine C=NH isosteres (C=O/C=S) were inactive. Monomeric analogues were 16-64 mu g mL(-1) active against MRSA and VRE. An analogue that lacks the terminal hydrazide NH moiety showed modest Gram-negative activity at 64 mu g mL(-1). A 4-tert-butyl analogue was shown to be active against both Gram-positive and -negative strains at 16-64 mu g mL(-1). In general, additional modifications with aromatic moieties was poorly tolerated, except with concomitant introduction of an imine C-alkyl group. The activity of these analogues against MRSA and VRE ranged from 8 mu g mL(-1) to inactive (MIC>128 mu g mL(-1)) with the naphthyl and indole analogues. Gram-negative activity was most promising with two compounds at 16 mu g mL(-1) against E. coli. Against P. aeruginosa, the highest activity observed was with MIC values of 32 mu g mL(-1) with another two analogues. Combined, these findings support the further development of the (E)-2-benzylidenehydrazine-1-carboximidamide scaffold as a promising scaffold for the development of antibiotics against Gram-positive and Gram-negative strains. Refereed/Peer-reviewed
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- 2018
27. 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
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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, 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, and Ogunniyi, Abiodun D
- Subjects
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 - Abstract
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
- Published
- 2020
28. In vitro antimicrobial activity of robenidine, ethylenediaminetetraacetic acid and polymyxin B nonapeptide against important human and veterinary pathogens
- Author
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Sanjay Garg, Hongfei Pi, Jowenna Xiao Feng Sim, Peter B. Hill, Henrietta Venter, Adam McCluskey, Wei Yee Chan, Stephen W. Page, Manouchehr Khazandi, Darren J. Trott, Abiodun D. Ogunniyi, Khazandi, Manouchehr, Pi, Hongfei, Chan, Wei Yee, Ogunniyi, Abiodun David, Sim, Jowenna Xiao Feng, Venter, Henrietta, Garg, Sanjay, Page, Stephen W, Hill, Peter B, McCluskey, Adam, and Trott, Darren J
- Subjects
Microbiology (medical) ,Veterinary medicine ,lcsh:QR1-502 ,medicine.disease_cause ,Microbiology ,lcsh:Microbiology ,robenidine ,03 medical and health sciences ,chemistry.chemical_compound ,Antibiotic resistance ,Robenidine ,medicine ,canine otitis externa ,030304 developmental biology ,Original Research ,combination ,0303 health sciences ,biology ,030306 microbiology ,Pseudomonas aeruginosa ,Chemistry ,EDTA ,Acinetobacter ,biology.organism_classification ,Antimicrobial ,Acinetobacter baumannii ,antimicrobial ,Acinetobacter calcoaceticus ,Antibacterial activity - Abstract
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 in vitro using microdilution susceptibility testing and the checkerboard method. Fractional inhibitory concentration indices (FICIs) and dose reduction indices (DRI) of the combinations against tested isolates were determined. Robenidine alone was bactericidal against Acinetobacter baumannii [minimum inhibitory concentrations (MIC) mode = 8 μg/ml] and Acinetobacter calcoaceticus (MIC mode = 2 μg/ml). Against Acinetobacter spp., an additivity/indifference of the combination of robenidine/EDTA (0.53 > FICIs > 1.06) and a synergistic effect of the combination of robenidine/PMBN (0.5 < FICI) were obtained. DRIs of robenidine were significantly increased in the presence of both EDTA and PMBN from 2- to 2048-fold. Robenidine exhibited antimicrobial activity against Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa, in the presence of sub-inhibitory concentrations of either EDTA or PMBN. Robenidine also demonstrated potent antibacterial activity against multidrug-resistant Gram-positive pathogens and all Gram-negative pathogens isolated from cases of canine otitis externa in the presence of EDTA. Robenidine did not demonstrate antibiofilm activity against Gram-positive and Gram-negative bacteria. EDTA facilitated biofilm biomass degradation for both Gram-positives and Gram-negatives. The addition of robenidine to EDTA was not associated with any change in the effect on biofilm biomass degradation. The combination of robenidine with EDTA or PMBN has potential for further exploration and pharmaceutical development, such as incorporation into topical and otic formulations for animal and human use. Refereed/Peer-reviewed
- Published
- 2019
29. Key Considerations in Designing Oral Drug Delivery Systems for Dogs
- Author
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Pooi Yin Wong, Stephen W. Page, Yunmei Song, Karl F. Peressin, Sanjay Garg, Song, Yunmei, Peressin, Karl, Wong, Pooi Yin, Page, Stephen W, and Garg, Sanjay
- Subjects
medicine.medical_specialty ,Veterinary Drugs ,oral drug delivery ,040301 veterinary sciences ,Administration, Oral ,Biological Availability ,Pharmaceutical Science ,030226 pharmacology & pharmacy ,0403 veterinary science ,03 medical and health sciences ,Dogs ,Drug Delivery Systems ,0302 clinical medicine ,Species Specificity ,oral absorption ,medicine ,Animals ,gastrointestinal transit ,in vitro/in vivo correlations ,Intensive care medicine ,in vitro models ,ADME ,business.industry ,Gastrointestinal transit ,Biopharmaceutics Classification System ,04 agricultural and veterinary sciences ,Biotechnology ,Gastrointestinal Tract ,Biopharmaceutical ,Gastric Emptying ,Pharmaceutical Preparations ,Drug Design ,business ,Oral retinoid - Abstract
The present review discusses the pharmaceutical impact of the anatomy and physiology of the canine gastrointestinal tract to provide a comprehensive guide to the theories and challenges associated with the development of oral drug delivery systems for dogs. Novel pharmaceutical technologies applied to veterinary drugs are discussed indicating the advantages and benefits for animals. There are currently immense research and development efforts being funneled into novel canine health products. Such products are being used to overcome limitations of drugs that display site-dependent absorption or possess poor biopharmaceutical properties. Techniques that are employed to increase bioavailability of the Biopharmaceutics Classification System class II drugs are discussed in this article. Furthermore, an overview of palatable oral formulations for dog care is provided as an approach to easy administration. In vitro and in vivo evaluation and correlation of oral drug formulations in dogs are also addressed. This article assesses the outlook of canine oral drug development recognizing substantial growth forecasts of the dog care market. Refereed/Peer-reviewed
- Published
- 2016
30. Bioluminescent murine models of bacterial sepsis and scald wound infections for antimicrobial efficacy testing
- Author
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Katherine Belov, Abiodun D. Ogunniyi, Manouchehr Khazandi, Peter B. Hill, Sanjay Garg, Zlatko Kopecki, Stephen W. Page, Alexandra R Boileau, Darren J. Trott, Henrietta Venter, Emma Peel, Allison J. Cowin, Wei Yee Chan, Elizabeth E. Hickey, Ogunniyi, Abiodun D, Kopecki, Zlatko, Hickey, Elizabeth E, Khazandi, Manouchehr, Peel, Emma, Belov, Katherine, Boileau, Alexandra, Garg, Sanjay, Venter, Henrietta, Chan, Wei Yee, Hill, Peter B, Page, Stephen W, Cowin, Allison J, and Trott, Darren J
- Subjects
0301 basic medicine ,Male ,Bacterial Diseases ,Physiology ,Staphylococcus ,lcsh:Medicine ,Bacteremia ,Disease ,medicine.disease_cause ,Pathology and Laboratory Medicine ,sepsis ,chemistry.chemical_compound ,Mice ,Medicine and Health Sciences ,lcsh:Science ,Multidisciplinary ,Physics ,Animal Models ,Staphylococcal Infections ,3. Good health ,Anti-Bacterial Agents ,Bacterial Pathogens ,Mupirocin ,Infectious Diseases ,Experimental Organism Systems ,Staphylococcus aureus ,Medical Microbiology ,Physical Sciences ,Pathogens ,Burns ,Elementary Particles ,medicine.drug ,Research Article ,030106 microbiology ,Mouse Models ,Microbial Sensitivity Tests ,Staphylococcal infections ,Research and Analysis Methods ,Microbiology ,antimicrobials ,Sepsis ,03 medical and health sciences ,Model Organisms ,Signs and Symptoms ,Diagnostic Medicine ,Tissue Repair ,medicine ,Animals ,Animal Models of Disease ,Particle Physics ,Microbial Pathogens ,Photons ,Bacteria ,business.industry ,lcsh:R ,Organisms ,Biology and Life Sciences ,medicine.disease ,Disease Models, Animal ,Luminescent Proteins ,Animal Models of Infection ,wound infections ,chemistry ,bacterial infections ,Concomitant ,Wound Infection ,Animal Studies ,lcsh:Q ,Daptomycin ,business ,Physiological Processes - Abstract
There are very few articles in the literature describing continuous models of bacterial infections that mimic disease pathogenesis in humans and animals without using separate cohorts of animals at each stage of disease. In this work, we developed bioluminescent mouse models of partial-thickness scald wound infection and sepsis that mimic disease pathogenesis in humans and animals using a recombinant luciferase-expressing Staphylococcus aureus strain (Xen29). Two days post-scald wound infection, mice were treated twice daily with a 2% topical mupirocin ointment for 7 days. For sepsis experiments, mice were treated intraperitoneally with 6 mg/kg daptomycin 2 h and 6 h post-infection and time to moribund monitored for 72 h. Consistent bacterial burden data were obtained from individual mice by regular photon intensity quantification on a Xenogen IVIS Lumina XRMS Series III biophotonic imaging system, with concomitant significant reduction in photon intensities in drug-treated mice. Post-mortem histopathological examination of wounds and bacterial counts in blood correlated closely with disease severity and total flux obtained from Xen29. The bioluminescent murine models provide a refinement to existing techniques of multiple bacterial enumeration during disease pathogenesis and promote animal usage reduction. The models also provide an efficient and information-rich platform for preclinical efficacy evaluation of new drug classes for treating acute and chronic human and animal bacterial infections. Refereed/Peer-reviewed
- Published
- 2018
31. Evaluation of transdermal drug permeation as modulated by lipoderm and pluronic lecithin organogel
- Author
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Stephen W. Page, Yunmei Song, Qian Zhang, Sanjay Garg, Zhang, Qian, Song, Yunmei, Page, Stephen W, and Garg, Sanjay
- Subjects
food.ingredient ,Swine ,Chemistry, Pharmaceutical ,Skin Absorption ,Pharmaceutical Science ,02 engineering and technology ,Poloxamer ,Administration, Cutaneous ,030226 pharmacology & pharmacy ,Lecithin ,Permeability ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,food ,Drug Delivery Systems ,Lecithins ,Animals ,Solubility ,Fluorescein ,Transdermal ,Skin ,Chromatography ,integumentary system ,Dimethyl sulfoxide ,solubility ,permeation enhancers ,imaging method ,Penetration (firestop) ,021001 nanoscience & nanotechnology ,transdermal drug delivery ,chemistry ,percutaneous ,Lipophilicity ,0210 nano-technology - Abstract
The transdermal delivery of 2 fluorescent probes with similar molecular weight but different lipophilicity, into and through the skin from 2 commercially available transdermal bases, pluronic lecithin organogel, and Lipoderm ® has been evaluated. First, in vitro penetration of fluorescein sodium and fluorescein (free acid) through porcine skin was evaluated. Retention and depth distribution profiles in skin were obtained by tape stripping and then followed by optical sectioning using multiphoton microscopy. The results showed that Lipoderm ® led to an enhanced penetration of the hydrophilic compound, fluorescein sodium. For the lipophilic compound fluorescein (free acid), Lipoderm ® performed similar to pluronic lecithin organogel base, where minimal drug was detected in either receptor phase. The skin retention and depth distribution results also showed that the hydrophilic fluorescein sodium had high skin retention with Lipoderm ® , whereas fluorescein (free acid) had very low penetration and retention with increasing skin depth. Moreover, optical sectioning by multiphoton microscopy revealed an uneven distribution of probes across the skin in the x-y plane for both transdermal bases. This work showed that a hydrophilic compound has significantly increased skin penetration and retention when formulated with Lipoderm ® , and the skin retention of the probe was the main determinant of its skin flux. Refereed/Peer-reviewed
- Published
- 2018
32. Repurposing Ionophores as novel antimicrobial agents for the treatment of bovine mastitis caused by Gram-positive pathogens
- Author
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Abiodun D. Ogunniyi, Kiro R. Petrovski, Elizabeth E. Hickey, Ryan O’Handley, Manouchehr Khazandi, Stephen W. Page, Sanjay Garg, Darren J. Trott, Hui San Wong, Hickey, Elizabeth E, Wong, Hui San, Khazandi, Manouchehr, Ogunniyi, Abiodun D, Petrovski, Kiro R, Garg, Sanjay, Page, Stephen W, O'Handley, Ryan, and Trott, Darren J
- Subjects
0301 basic medicine ,Lasalocid ,Staphylococcus ,030106 microbiology ,Narasin ,Microbial Sensitivity Tests ,Gram-Positive Bacteria ,medicine.disease_cause ,mastitis ,Microbiology ,03 medical and health sciences ,chemistry.chemical_compound ,Gram-positive ,Antibiotic resistance ,Streptococcal Infections ,medicine ,Animals ,Monensin ,Mastitis, Bovine ,Salinomycin ,Pyrans ,Pharmacology ,General Veterinary ,Ionophores ,Streptococcus ,Staphylococcal Infections ,Haemolysis ,Antimicrobial ,methicillin-resistant ,Anti-Bacterial Agents ,3. Good health ,030104 developmental biology ,chemistry ,Staphylococcus aureus ,Biofilms ,cytotoxicity ,Cattle ,Female ,biofilms - Abstract
Increasing reports of multidrug-resistant bacterial infections in animals has created a need for novel antimicrobial agents that do not promote cross-resistance to critically important antimicrobial classes used in human medicine. In response to the recent emergence of antimicrobial resistance in several bovine mastitis pathogens, in vitro antimicrobial susceptibility was determined for four polyether ionophores (lasalocid, monensin, narasin and salinomycin) against Staphylococcus spp. and Streptococcus spp. isolated from clinical cases. In addition, erythrocyte haemolysis and WST-1 cell proliferation assays were used to assess in vitro mammalian cell cytotoxicity and biofilm susceptibility testing was performed using the minimum biofilm eradication concentration(MBEC™) biofilm assay. Lasalocid, monensin, narasin and salinomycin exhibited bacteriostatic antimicrobial activity against all pathogens tested, including methicillin-resistant staphylococci, with MIC90 values
- Published
- 2018
33. Evaluation of robenidine analog NCL195 as a novel broad-spectrum antibacterial agent
- Author
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Hérida Regina Nunes Salgado, Sanjay Garg, Andrew Stevens, Geoffrey W. Coombs, Hongfei Pi, Abiodun D. Ogunniyi, Eliane Gandolpho Tótoli, Dean L. Shinabarger, Geraldine Laven-Law, Manouchehr Khazandi, Kiro R. Petrovski, James C. Paton, Karen L. White, Sarah K. Sims, Darren J. Trott, Adam McCluskey, Andrew K. Powell, Henrietta Venter, John D. Turnidge, Stephen W. Page, Ogunniyi, Abiodun D, Khazandi, Manouchehr, Stevens, Andrew J, Sims, Sarah K, Page, Stephen W, Garg, Sanjay, Venter, Henrietta, Powell, Andrew, White, Karen, Petrovski, Kiro R, Laven-Law, Geraldine, Tótoli, Eliane G, Salgado, Hérida R, Pi, Hongfei, Coombs, Geoffrey W, Shinabarger, Dean L, Turnidge, John D, Paton, James C, McCluskey, Adam, Trott, Darren J, Univ Adelaide, Univ Newcastle, Neoculi Pty Ltd, Univ South Australia, Monash Univ, Universidade Estadual Paulista (Unesp), Fiona Stanley Hosp, Murdoch Univ, and Micromyx LLC
- Subjects
0301 basic medicine ,Time Factors ,Physiology ,Polymyxin ,Staphylococcus ,Cell Membranes ,lcsh:Medicine ,medicine.disease_cause ,Pathology and Laboratory Medicine ,chemistry.chemical_compound ,Mice ,Medicine and Health Sciences ,lcsh:Science ,Antibacterial agent ,Multidisciplinary ,Antimicrobials ,Drugs ,Pneumococcus ,Antimicrobial ,3. Good health ,Anti-Bacterial Agents ,Bacterial Pathogens ,Body Fluids ,Electrophysiology ,Streptococcus pneumoniae ,Blood ,Medical Microbiology ,Microsomes, Liver ,Pathogens ,Cellular Structures and Organelles ,Anatomy ,Research Article ,Staphylococcus aureus ,Gram-negative bacteria ,Robenidine ,medicine.drug_class ,030106 microbiology ,Microbial Sensitivity Tests ,Biology ,Hemolysis ,Microbiology ,Membrane Potential ,Blood Plasma ,Cell Line ,03 medical and health sciences ,Structure-Activity Relationship ,Antibiotic resistance ,Vancomycin ,Microbial Control ,Drug Resistance, Bacterial ,medicine ,Animals ,Humans ,Microbial Pathogens ,Pharmacology ,Bacteria ,Pseudomonas aeruginosa ,Cell Membrane ,lcsh:R ,Organisms ,Biology and Life Sciences ,Streptococcus ,Cell Biology ,biology.organism_classification ,Multiple drug resistance ,chemistry ,lcsh:Q ,Antimicrobial Resistance ,Enterococcus - Abstract
Made available in DSpace on 2018-11-26T17:40:30Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-09-05 Australian Research Council (ARC) Neoculi Pty Ltd National Health and Medical Research Council of Australia (NHMRC) University of South Australia Sansom Institute of Health Research Micromyx LLC 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. NCL195 was less cytotoxic to mammalian cell lines than the parent compound, showed low metabolic degradation rates by human and mouse liver microsomes, and exhibited high plasma concentration and low plasma clearance rates in mice. NCL195 was bactericidal against Acinetobacter spp and Neisseria meningitidis and also demonstrated potent activity against A. baumannii, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae and Enterobacter spp. in the presence of sub-inhibitory concentrations of ethylenediaminetetraacetic acid (EDTA) and polymyxin B. These findings demonstrate that NCL195 represents a new chemical lead for further medicinal chemistry and pharmaceutical development to enhance potency, solubility and selectivity against serious bacterial pathogens. Univ Adelaide, Sch Anim & Vet Sci, Australian Ctr Antimicrobial Resistance Ecol, Roseworthy, SA, Australia Univ Newcastle, Sch Environm & Life Sci, Chem, Callaghan, NSW, Australia Univ Adelaide, Sch Anim & Vet Sci, Roseworthy, SA, Australia Neoculi Pty Ltd, Burwood, Vic, Australia Univ South Australia, Sansom Inst Hlth Res, Sch Pharm & Med Sci, Ctr Pharmaceut Innovat & Dev, Adelaide, SA, Australia Univ South Australia, Sansom Inst Hlth Res, Sch Pharm & Med Sci, Adelaide, SA, Australia Monash Univ, Monash Inst Pharmaceut Sci, Ctr Drug Candidate Optimisat, Parkville, Vic, Australia Sao Paulo State Univ, Sch Pharmaceut Sci, Dept Drugs & Med, Sao Paulo, Brazil Fiona Stanley Hosp, Path West Lab Med WA, Dept Microbiol, Murdoch, WA, Australia Murdoch Univ, Sch Vet & Life Sci, Murdoch, WA, Australia Micromyx LLC, Kalamazoo, MI USA Univ Adelaide, Sch Biol Sci, Dept Mol & Cellular Biol, Adelaide, SA, Australia Univ Adelaide, Sch Biol Sci, Dept Mol & Cellular Biol, Res Ctr Infect Dis, Adelaide, SA, Australia Sao Paulo State Univ, Sch Pharmaceut Sci, Dept Drugs & Med, Sao Paulo, Brazil Australian Research Council (ARC): LP110200770 National Health and Medical Research Council of Australia (NHMRC): 565526 National Health and Medical Research Council of Australia (NHMRC): 627142
- Published
- 2017
34. Development of intramammary delivery systems containing lasalocid for the treatment of bovine mastitis: impact of solubility improvement on safety, efficacy, and milk distribution in dairy cattle
- Author
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Sanjay Garg, Darren J. Trott, Kiro R. Petrovski, Hui San Wong, Yunmei Song, Wen Wang, Jeanette Perry, Stephen W. Page, Patricia Eats, Wang, Wen, Song, Yunmei, Petrovski, Kiro, Eats, Patricia, Trott, Darren, Wong, Hui San, Page, Stephen W, Perry, Jeanette, and Garg, Sanjay
- Subjects
Lasalocid ,Chemistry, Pharmaceutical ,intramammary drug delivery system ,Pharmaceutical Science ,Microbial Sensitivity Tests ,methicillin-resistant Staphylococcus aureus ,medicine.disease_cause ,chemistry.chemical_compound ,Cloxacillin ,Mammary Glands, Animal ,Streptococcal Infections ,Drug Discovery ,Spectroscopy, Fourier Transform Infrared ,medicine ,Animals ,Food science ,Mastitis, Bovine ,Dairy cattle ,Original Research ,Pharmacology ,Streptococcus uberis ,ionophore ,solid dispersion ,Drug Design, Development and Therapy ,biology ,Calorimetry, Differential Scanning ,Chemistry ,Drug Administration Routes ,Povidone ,medicine.disease ,biology.organism_classification ,Antimicrobial ,Methicillin-resistant Staphylococcus aureus ,Mastitis ,Anti-Bacterial Agents ,Dairying ,Kinetics ,Milk ,superbugs ,Solubility ,Staphylococcus aureus ,Immunology ,Nanoparticles ,Cattle ,Female ,medicine.drug - Abstract
Wen Wang,1 Yunmei Song,1 Kiro Petrovski,2 Patricia Eats,2 Darren J Trott,2 Hui San Wong,2 Stephen W Page,3 Jeanette Perry,2 Sanjay Garg11School of Pharmacy and Medical Science, University of South Australia, Adelaide, SA, Australia; 2School of Animal and Veterinary Sciences, University of Adelaide, Adelaide, SA, Australia; 3Luoda Pharma Pty Ltd, Caringbah, NSW, AustraliaBackground: Mastitis is a major disease of dairy cattle. Given the recent emergence of methicillin-resistant Staphylococcus aureus as a cause of bovine mastitis, new intramammary (IMA) treatments are urgently required. Lasalocid, a member of the polyether ionophore class of antimicrobial agents, has not been previously administered to cows by the IMA route and has favorable characteristics for development as a mastitis treatment. This study aimed to develop an IMA drug delivery system (IMDS) of lasalocid for the treatment of bovine mastitis.Methods: Minimum inhibitory concentrations (MICs) were determined applying the procedures recommended by the Clinical and Laboratory Standards Institute. Solid dispersions (SDs) of lasalocid were prepared and characterized using differential scanning calorimetry and Fourier transform infrared spectroscopy. IMDSs containing lasalocid of micronized, nano-sized, or as SD form were tested for their IMA safety in cows. Therapeutic efficacy of lasalocid IMDSs was tested in a bovine model involving experimental IMA challenge with the mastitis pathogen Streptococcus uberis.Results: Lasalocid demonstrated antimicrobial activity against the major Gram-positive mastitis pathogens including S. aureus (MIC range 0.5–8µg/mL). The solubility test confirmed limited, ion-strength-dependent water solubility of lasalocid. A kinetic solubility study showed that SDs effectively enhanced water solubility of lasalocid (21–35-fold). Polyvinylpyrrolidone (PVP)-lasalocid SD caused minimum mammary irritation in treated cows and exhibited faster distribution in milk than either nano or microsized lasalocid. IMDSs with PVP-lasalocid SD provided effective treatment with a higher mastitis clinical and microbiological cure rate (66.7%) compared to cloxacillin (62.5%).Conclusion: Lasalocid SD IMDS provided high cure rates and effectiveness in treating bovine mastitis with acceptable safety in treated cows.Keywords: ionophore, methicillin-resistant Staphylococcus aureus, solid dispersion, intramammary drug delivery system, superbugs
- Published
- 2015
35. Development of intramammary delivery systems containing lasalocid for the treatment of bovine mastitis: impact of solubility improvement on safety, efficacy, and milk distribution in dairy cattle.
- Author
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Wang W, Song Y, Petrovski K, Eats P, Trott DJ, Wong HS, Page SW, Perry J, and Garg S
- Subjects
- Animals, Anti-Bacterial Agents adverse effects, Anti-Bacterial Agents chemistry, Anti-Bacterial Agents metabolism, Calorimetry, Differential Scanning, Cattle, Chemistry, Pharmaceutical, Drug Administration Routes, Female, Kinetics, Lasalocid adverse effects, Lasalocid chemistry, Lasalocid metabolism, Mammary Glands, Animal microbiology, Mammary Glands, Animal physiopathology, Mastitis, Bovine diagnosis, Mastitis, Bovine microbiology, Mastitis, Bovine physiopathology, Microbial Sensitivity Tests, Milk metabolism, Nanoparticles, Povidone chemistry, Solubility, Spectroscopy, Fourier Transform Infrared, Streptococcal Infections diagnosis, Streptococcal Infections microbiology, Streptococcal Infections physiopathology, Anti-Bacterial Agents administration & dosage, Dairying, Lasalocid administration & dosage, Mammary Glands, Animal drug effects, Mastitis, Bovine drug therapy, Streptococcal Infections drug therapy
- Abstract
Background: Mastitis is a major disease of dairy cattle. Given the recent emergence of methicillin-resistant Staphylococcus aureus as a cause of bovine mastitis, new intramammary (IMA) treatments are urgently required. Lasalocid, a member of the polyether ionophore class of antimicrobial agents, has not been previously administered to cows by the IMA route and has favorable characteristics for development as a mastitis treatment. This study aimed to develop an IMA drug delivery system (IMDS) of lasalocid for the treatment of bovine mastitis., Methods: Minimum inhibitory concentrations (MICs) were determined applying the procedures recommended by the Clinical and Laboratory Standards Institute. Solid dispersions (SDs) of lasalocid were prepared and characterized using differential scanning calorimetry and Fourier transform infrared spectroscopy. IMDSs containing lasalocid of micronized, nano-sized, or as SD form were tested for their IMA safety in cows. Therapeutic efficacy of lasalocid IMDSs was tested in a bovine model involving experimental IMA challenge with the mastitis pathogen Streptococcus uberis., Results: Lasalocid demonstrated antimicrobial activity against the major Gram-positive mastitis pathogens including S. aureus (MIC range 0.5-8 μg/mL). The solubility test confirmed limited, ion-strength-dependent water solubility of lasalocid. A kinetic solubility study showed that SDs effectively enhanced water solubility of lasalocid (21-35-fold). Polyvinylpyrrolidone (PVP)-lasalocid SD caused minimum mammary irritation in treated cows and exhibited faster distribution in milk than either nano or microsized lasalocid. IMDSs with PVP-lasalocid SD provided effective treatment with a higher mastitis clinical and microbiological cure rate (66.7%) compared to cloxacillin (62.5%)., Conclusion: Lasalocid SD IMDS provided high cure rates and effectiveness in treating bovine mastitis with acceptable safety in treated cows.
- Published
- 2015
- Full Text
- View/download PDF
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