Cargando…

Activity and Predicted Nephrotoxicity of Synthetic Antibiotics Based on Polymyxin B

[Image: see text] The polymyxin lipodecapeptides colistin and polymyxin B have become last resort therapies for infections caused by highly drug-resistant Gram-negative bacteria. Unfortunately, their utility is compromised by significant nephrotoxicity and polymyxin-resistant bacterial strains. We h...

Descripción completa

Detalles Bibliográficos
Autores principales: Gallardo-Godoy, Alejandra, Muldoon, Craig, Becker, Bernd, Elliott, Alysha G., Lash, Lawrence H., Huang, Johnny X., Butler, Mark S., Pelingon, Ruby, Kavanagh, Angela M., Ramu, Soumya, Phetsang, Wanida, Blaskovich, Mark A. T., Cooper, Matthew A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2016
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4774972/
https://www.ncbi.nlm.nih.gov/pubmed/26734854
http://dx.doi.org/10.1021/acs.jmedchem.5b01593
_version_ 1782418997964177408
author Gallardo-Godoy, Alejandra
Muldoon, Craig
Becker, Bernd
Elliott, Alysha G.
Lash, Lawrence H.
Huang, Johnny X.
Butler, Mark S.
Pelingon, Ruby
Kavanagh, Angela M.
Ramu, Soumya
Phetsang, Wanida
Blaskovich, Mark A. T.
Cooper, Matthew A.
author_facet Gallardo-Godoy, Alejandra
Muldoon, Craig
Becker, Bernd
Elliott, Alysha G.
Lash, Lawrence H.
Huang, Johnny X.
Butler, Mark S.
Pelingon, Ruby
Kavanagh, Angela M.
Ramu, Soumya
Phetsang, Wanida
Blaskovich, Mark A. T.
Cooper, Matthew A.
author_sort Gallardo-Godoy, Alejandra
collection PubMed
description [Image: see text] The polymyxin lipodecapeptides colistin and polymyxin B have become last resort therapies for infections caused by highly drug-resistant Gram-negative bacteria. Unfortunately, their utility is compromised by significant nephrotoxicity and polymyxin-resistant bacterial strains. We have conducted a systematic activity–toxicity investigation by varying eight of the nine polymyxin amino acid free side chains, preparing over 30 analogues using a novel solid-phase synthetic route. Compounds were tested against a panel of Gram-negative bacteria and counter-screened for in vitro cell toxicity. Promising compounds underwent additional testing against primary kidney cells isolated from human kidneys to better predict their nephrotoxic potential. Many of the new compounds possessed equal or better antimicrobial potency compared to polymyxin B, and some were less toxic than polymyxin B and colistin against mammalian HepG2 cells and human primary kidney cells. These initial structure–activity and structure–toxicity studies set the stage for further improvements to the polymyxin class of antibiotics.
format Online
Article
Text
id pubmed-4774972
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher American Chemical Society
record_format MEDLINE/PubMed
spelling pubmed-47749722016-03-03 Activity and Predicted Nephrotoxicity of Synthetic Antibiotics Based on Polymyxin B Gallardo-Godoy, Alejandra Muldoon, Craig Becker, Bernd Elliott, Alysha G. Lash, Lawrence H. Huang, Johnny X. Butler, Mark S. Pelingon, Ruby Kavanagh, Angela M. Ramu, Soumya Phetsang, Wanida Blaskovich, Mark A. T. Cooper, Matthew A. J Med Chem [Image: see text] The polymyxin lipodecapeptides colistin and polymyxin B have become last resort therapies for infections caused by highly drug-resistant Gram-negative bacteria. Unfortunately, their utility is compromised by significant nephrotoxicity and polymyxin-resistant bacterial strains. We have conducted a systematic activity–toxicity investigation by varying eight of the nine polymyxin amino acid free side chains, preparing over 30 analogues using a novel solid-phase synthetic route. Compounds were tested against a panel of Gram-negative bacteria and counter-screened for in vitro cell toxicity. Promising compounds underwent additional testing against primary kidney cells isolated from human kidneys to better predict their nephrotoxic potential. Many of the new compounds possessed equal or better antimicrobial potency compared to polymyxin B, and some were less toxic than polymyxin B and colistin against mammalian HepG2 cells and human primary kidney cells. These initial structure–activity and structure–toxicity studies set the stage for further improvements to the polymyxin class of antibiotics. American Chemical Society 2016-01-06 2016-02-11 /pmc/articles/PMC4774972/ /pubmed/26734854 http://dx.doi.org/10.1021/acs.jmedchem.5b01593 Text en Copyright © 2016 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
spellingShingle Gallardo-Godoy, Alejandra
Muldoon, Craig
Becker, Bernd
Elliott, Alysha G.
Lash, Lawrence H.
Huang, Johnny X.
Butler, Mark S.
Pelingon, Ruby
Kavanagh, Angela M.
Ramu, Soumya
Phetsang, Wanida
Blaskovich, Mark A. T.
Cooper, Matthew A.
Activity and Predicted Nephrotoxicity of Synthetic Antibiotics Based on Polymyxin B
title Activity and Predicted Nephrotoxicity of Synthetic Antibiotics Based on Polymyxin B
title_full Activity and Predicted Nephrotoxicity of Synthetic Antibiotics Based on Polymyxin B
title_fullStr Activity and Predicted Nephrotoxicity of Synthetic Antibiotics Based on Polymyxin B
title_full_unstemmed Activity and Predicted Nephrotoxicity of Synthetic Antibiotics Based on Polymyxin B
title_short Activity and Predicted Nephrotoxicity of Synthetic Antibiotics Based on Polymyxin B
title_sort activity and predicted nephrotoxicity of synthetic antibiotics based on polymyxin b
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4774972/
https://www.ncbi.nlm.nih.gov/pubmed/26734854
http://dx.doi.org/10.1021/acs.jmedchem.5b01593
work_keys_str_mv AT gallardogodoyalejandra activityandpredictednephrotoxicityofsyntheticantibioticsbasedonpolymyxinb
AT muldooncraig activityandpredictednephrotoxicityofsyntheticantibioticsbasedonpolymyxinb
AT beckerbernd activityandpredictednephrotoxicityofsyntheticantibioticsbasedonpolymyxinb
AT elliottalyshag activityandpredictednephrotoxicityofsyntheticantibioticsbasedonpolymyxinb
AT lashlawrenceh activityandpredictednephrotoxicityofsyntheticantibioticsbasedonpolymyxinb
AT huangjohnnyx activityandpredictednephrotoxicityofsyntheticantibioticsbasedonpolymyxinb
AT butlermarks activityandpredictednephrotoxicityofsyntheticantibioticsbasedonpolymyxinb
AT pelingonruby activityandpredictednephrotoxicityofsyntheticantibioticsbasedonpolymyxinb
AT kavanaghangelam activityandpredictednephrotoxicityofsyntheticantibioticsbasedonpolymyxinb
AT ramusoumya activityandpredictednephrotoxicityofsyntheticantibioticsbasedonpolymyxinb
AT phetsangwanida activityandpredictednephrotoxicityofsyntheticantibioticsbasedonpolymyxinb
AT blaskovichmarkat activityandpredictednephrotoxicityofsyntheticantibioticsbasedonpolymyxinb
AT coopermatthewa activityandpredictednephrotoxicityofsyntheticantibioticsbasedonpolymyxinb