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Evaluation of Homogentisic Acid, a Prospective Antibacterial Agent Highlighted by the Suitability of Nitisinone in Alkaptonuria 2 (SONIA 2) Clinical Trial

Despite urgent warnings about the spread of multidrug-resistant bacteria, the antibiotic development pipeline has remained sparsely populated. Naturally occurring antibacterial compounds may provide novel chemical starting points for antibiotic development programs and should be actively sought out....

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Autores principales: Ooi, Nicola, Cooper, Ian R., Norman, Brendan, Gallagher, James A., Sireau, Nick, Bou-Gharios, George, Ranganath, Lakshminarayan R., Savage, Victoria J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10341174/
https://www.ncbi.nlm.nih.gov/pubmed/37443717
http://dx.doi.org/10.3390/cells12131683
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author Ooi, Nicola
Cooper, Ian R.
Norman, Brendan
Gallagher, James A.
Sireau, Nick
Bou-Gharios, George
Ranganath, Lakshminarayan R.
Savage, Victoria J.
author_facet Ooi, Nicola
Cooper, Ian R.
Norman, Brendan
Gallagher, James A.
Sireau, Nick
Bou-Gharios, George
Ranganath, Lakshminarayan R.
Savage, Victoria J.
author_sort Ooi, Nicola
collection PubMed
description Despite urgent warnings about the spread of multidrug-resistant bacteria, the antibiotic development pipeline has remained sparsely populated. Naturally occurring antibacterial compounds may provide novel chemical starting points for antibiotic development programs and should be actively sought out. Evaluation of homogentisic acid (HGA), an intermediate in the tyrosine degradation pathway, showed that the compound had innate activity against Gram-positive and Gram-negative bacteria, which was lost following conversion into the degradation product benzoquinone acetic acid (BQA). Anti-staphylococcal activity of HGA can be attributed to effects on bacterial membranes. Despite an absence of haemolytic activity, the compound was cytotoxic to human HepG2 cells. We conclude that the antibacterial activity and in vitro safety profile of HGA render it more suitable for use as a topical agent or for inclusion in a small-molecule medicinal chemistry program.
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spelling pubmed-103411742023-07-14 Evaluation of Homogentisic Acid, a Prospective Antibacterial Agent Highlighted by the Suitability of Nitisinone in Alkaptonuria 2 (SONIA 2) Clinical Trial Ooi, Nicola Cooper, Ian R. Norman, Brendan Gallagher, James A. Sireau, Nick Bou-Gharios, George Ranganath, Lakshminarayan R. Savage, Victoria J. Cells Communication Despite urgent warnings about the spread of multidrug-resistant bacteria, the antibiotic development pipeline has remained sparsely populated. Naturally occurring antibacterial compounds may provide novel chemical starting points for antibiotic development programs and should be actively sought out. Evaluation of homogentisic acid (HGA), an intermediate in the tyrosine degradation pathway, showed that the compound had innate activity against Gram-positive and Gram-negative bacteria, which was lost following conversion into the degradation product benzoquinone acetic acid (BQA). Anti-staphylococcal activity of HGA can be attributed to effects on bacterial membranes. Despite an absence of haemolytic activity, the compound was cytotoxic to human HepG2 cells. We conclude that the antibacterial activity and in vitro safety profile of HGA render it more suitable for use as a topical agent or for inclusion in a small-molecule medicinal chemistry program. MDPI 2023-06-21 /pmc/articles/PMC10341174/ /pubmed/37443717 http://dx.doi.org/10.3390/cells12131683 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Communication
Ooi, Nicola
Cooper, Ian R.
Norman, Brendan
Gallagher, James A.
Sireau, Nick
Bou-Gharios, George
Ranganath, Lakshminarayan R.
Savage, Victoria J.
Evaluation of Homogentisic Acid, a Prospective Antibacterial Agent Highlighted by the Suitability of Nitisinone in Alkaptonuria 2 (SONIA 2) Clinical Trial
title Evaluation of Homogentisic Acid, a Prospective Antibacterial Agent Highlighted by the Suitability of Nitisinone in Alkaptonuria 2 (SONIA 2) Clinical Trial
title_full Evaluation of Homogentisic Acid, a Prospective Antibacterial Agent Highlighted by the Suitability of Nitisinone in Alkaptonuria 2 (SONIA 2) Clinical Trial
title_fullStr Evaluation of Homogentisic Acid, a Prospective Antibacterial Agent Highlighted by the Suitability of Nitisinone in Alkaptonuria 2 (SONIA 2) Clinical Trial
title_full_unstemmed Evaluation of Homogentisic Acid, a Prospective Antibacterial Agent Highlighted by the Suitability of Nitisinone in Alkaptonuria 2 (SONIA 2) Clinical Trial
title_short Evaluation of Homogentisic Acid, a Prospective Antibacterial Agent Highlighted by the Suitability of Nitisinone in Alkaptonuria 2 (SONIA 2) Clinical Trial
title_sort evaluation of homogentisic acid, a prospective antibacterial agent highlighted by the suitability of nitisinone in alkaptonuria 2 (sonia 2) clinical trial
topic Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10341174/
https://www.ncbi.nlm.nih.gov/pubmed/37443717
http://dx.doi.org/10.3390/cells12131683
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