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4 results on '"anti-Wolbachia"'

1. Assessing Boron-Pleuromutilin AN11251 for the Development of Antibacterial Agents

Author

Ming-Jie Han, Miaomiao Pan, Genhui Xiao, Ying Yuan, Shawn Chen, and Zhiyang Zou

Subjects
pleuromutilins, AN11251, antibacterial, anti-Wolbachia, in vitro ADME, pharmacokinetics, Organic chemistry, QD241-441
Abstract

Pleuromutilins are a group of antibiotics derived from the naturally occurring compound. The recent approval of lefamulin for both intravenous and oral doses in humans to treat community-acquired bacterial pneumonia has prompted investigations in modifying the structure to broaden the antibacterial spectrum, enhance the activity, and improve the pharmacokinetic properties. AN11251 is a C(14)-functionalized pleuromutilin with a boron-containing heterocycle substructure. It was demonstrated to be an anti-Wolbachia agent with therapeutic potential for Onchocerciasis and lymphatic filariasis. Here, the in vitro and in vivo PK parameters of AN11251 were measured including PPB, intrinsic clearance, half-life, systemic clearance, and volume of distribution. The results indicate that the benzoxaborole-modified pleuromutilin possesses good ADME and PK properties. AN11251 has potent activities against the Gram-positive bacterial pathogens tested, including various drug-resistant strains, and against the slow-growing mycobacterial species. Finally, we employed PK/PD modeling to predict the human dose for treatment of disease caused by Wolbachia, Gram-positive bacteria, or Mycobacterium tuberculosis, which might facilitate the further development of AN11251.

Published
2023
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2. AWZ1066S, a highly specific anti-Wolbachia drug candidate for a short-course treatment of filariasis.

Author

Hong, W. David, Benayoud, Farid, Nixon, Gemma L., Ford, Louise, Johnston, Kelly L., Clare, Rachel H., Cassidy, Andrew, Cook, Darren A. N., Siu, Amy, Shiotani, Motohiro, Webborn, Peter J. H., Kavanagh, Stefan, Aljayyoussi, Ghaith, Murphy, Emma, Steven, Andrew, Archer, John, Struever, Dominique, Frohberger, Stefan J., Ehrens, Alexandra, and Hübner, Marc P.

Subjects
*ONCHOCERCIASIS, *ANTIPARASITIC agents, *TREATMENT of filariasis, *FILARIAL worms, *DRUG efficacy
Abstract

Onchocerciasis and lymphatic filariasis are two neglected tropical diseases that together affect ~157 million people and inflict severe disability. Both diseases are caused by parasitic filarial nematodes with elimination efforts constrained by the lack of a safe drug that can kill the adult filaria (macrofilaricide). Previous proof-of-concept human trials have demonstrated that depleting >90% of the essential nematode endosymbiont bacterium, Wolbachia, using antibiotics, can lead to permanent sterilization of adult female parasites and a safe macrofilaricidal outcome. AWZ1066S is a highly specific anti-Wolbachiacandidate selected through a lead optimization program focused on balancing efficacy, safety and drug metabolism/pharmacokinetic (DMPK) features of a thienopyrimidine/quinazoline scaffold derived from phenotypic screening. AWZ1066S shows superior efficacy to existing anti-Wolbachia therapies in validated preclinical models of infection and has DMPK characteristics that are compatible with a short therapeutic regimen of 7 days or less. This candidate molecule is well-positioned for onward development and has the potential to make a significant impact on communities affected by filariasis. [ABSTRACT FROM AUTHOR]

Published
2019
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3. AWZ1066S, a highly specific anti-Wolbachia drug candidate for a short-course treatment of filariasis

Author

Paul M. O'Neill, Edward W. Tate, W. David Hong, Adam P. Roberts, Marc P. Hübner, Peter J. H. Webborn, Mark J. Taylor, Alexandra Ehrens, Stefan J. Frohberger, Dominique Struever, John Archer, Farid Benayoud, Joseph D. Turner, Rachel H. Clare, Achim Hoerauf, Stefan Kavanagh, Fabian Gusovsky, Andrew Steven, Neil G. Berry, Kelly L. Johnston, Ghaith Aljayyoussi, Andrew Cassidy, Remigiusz A. Serwa, Suet C. Leung, Janet Hemingway, Alasdair T. M. Hubbard, Gemma L. Nixon, Amy Siu, Stephen A. Ward, Emma A Murphy, Louise Ford, Li Qie, Motohiro Shiotani, and Darren A. N. Cook

Subjects
0301 basic medicine, Drug, MACROFILARICIDAL ACTIVITY, Phenotypic screening, media_common.quotation_subject, 030231 tropical medicine, WUCHERERIA-BANCROFTI, medicine.disease_cause, Bioinformatics, drug discovery, Filariasis, DOUBLE-BLIND, 03 medical and health sciences, Macrofilaricide, chemistry.chemical_compound, 0302 clinical medicine, MD Multidisciplinary, medicine, BACTERIAL ENDOSYMBIONTS, macrofilaricide, lymphatic filariasis, ELIMINATION, Lymphatic filariasis, media_common, Science & Technology, LITOMOSOIDES-SIGMODONTIS, Multidisciplinary, biology, business.industry, onchocerciasis, ENDOBACTERIA, anti-Wolbachia, biology.organism_classification, medicine.disease, DOXYCYCLINE, Multidisciplinary Sciences, 030104 developmental biology, Wuchereria bancrofti, chemistry, Neglected tropical diseases, Science & Technology - Other Topics, Wolbachia, ALBENDAZOLE, business
Abstract

Onchocerciasis and lymphatic filariasis are two neglected tropical diseases that together affect ∼157 million people and inflict severe disability. Both diseases are caused by parasitic filarial nematodes with elimination efforts constrained by the lack of a safe drug that can kill the adult filaria (macrofilaricide). Previous proof-of-concept human trials have demonstrated that depleting >90% of the essential nematode endosymbiont bacterium, Wolbachia, using antibiotics, can lead to permanent sterilization of adult female parasites and a safe macrofilaricidal outcome. AWZ1066S is a highly specific anti-Wolbachia candidate selected through a lead optimization program focused on balancing efficacy, safety and drug metabolism/pharmacokinetic (DMPK) features of a thienopyrimidine/quinazoline scaffold derived from phenotypic screening. AWZ1066S shows superior efficacy to existing anti-Wolbachia therapies in validated preclinical models of infection and has DMPK characteristics that are compatible with a short therapeutic regimen of 7 days or less. This candidate molecule is well-positioned for onward development and has the potential to make a significant impact on communities affected by filariasis.

Published
2019

4. AWZ1066S, a highly specific anti

Author

W David, Hong, Farid, Benayoud, Gemma L, Nixon, Louise, Ford, Kelly L, Johnston, Rachel H, Clare, Andrew, Cassidy, Darren A N, Cook, Amy, Siu, Motohiro, Shiotani, Peter J H, Webborn, Stefan, Kavanagh, Ghaith, Aljayyoussi, Emma, Murphy, Andrew, Steven, John, Archer, Dominique, Struever, Stefan J, Frohberger, Alexandra, Ehrens, Marc P, Hübner, Achim, Hoerauf, Adam P, Roberts, Alasdair T M, Hubbard, Edward W, Tate, Remigiusz A, Serwa, Suet C, Leung, Li, Qie, Neil G, Berry, Fabian, Gusovsky, Janet, Hemingway, Joseph D, Turner, Mark J, Taylor, Stephen A, Ward, and Paul M, O'Neill

Subjects
Male, Pharmacology, onchocerciasis, Mice, SCID, Biological Sciences, anti-Wolbachia, Anti-Bacterial Agents, drug discovery, Mice, Elephantiasis, Filarial, Pyrimidines, Quinazolines, Animals, Female, macrofilaricide, lymphatic filariasis, Wolbachia
Abstract

Significance Onchocerciasis (river blindness) and lymphatic filariasis (elephantiasis) are neglected tropical diseases that cause severe disability and affect more than 157 million people globally. Current control efforts are hindered by the lack of a safe macrofilaricidal drug that can eliminate the parasitic adult nematodes safely. A clinically validated approach for delivering macrofilaricidal activity is to target the Wolbachia bacterial endosymbiont of the causative nematodes. This first-in-class and highly potent and specific anti-Wolbachia preclinical candidate molecule, AWZ1066S, has the potential to significantly impact current global onchocerciasis and lymphatic filariasis elimination programs and reduce elimination time frames from decades to years., Onchocerciasis and lymphatic filariasis are two neglected tropical diseases that together affect ∼157 million people and inflict severe disability. Both diseases are caused by parasitic filarial nematodes with elimination efforts constrained by the lack of a safe drug that can kill the adult filaria (macrofilaricide). Previous proof-of-concept human trials have demonstrated that depleting >90% of the essential nematode endosymbiont bacterium, Wolbachia, using antibiotics, can lead to permanent sterilization of adult female parasites and a safe macrofilaricidal outcome. AWZ1066S is a highly specific anti-Wolbachia candidate selected through a lead optimization program focused on balancing efficacy, safety and drug metabolism/pharmacokinetic (DMPK) features of a thienopyrimidine/quinazoline scaffold derived from phenotypic screening. AWZ1066S shows superior efficacy to existing anti-Wolbachia therapies in validated preclinical models of infection and has DMPK characteristics that are compatible with a short therapeutic regimen of 7 days or less. This candidate molecule is well-positioned for onward development and has the potential to make a significant impact on communities affected by filariasis.

Published
2019

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