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....
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-06-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/12/13/1683 |
| _version_ | 1797592000918192128 |
|---|---|
| author | Nicola Ooi Ian R. Cooper Brendan Norman James A. Gallagher Nick Sireau George Bou-Gharios Lakshminarayan R. Ranganath Victoria J. Savage |
| author_facet | Nicola Ooi Ian R. Cooper Brendan Norman James A. Gallagher Nick Sireau George Bou-Gharios Lakshminarayan R. Ranganath Victoria J. Savage |
| author_sort | Nicola Ooi |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-11T01:45:35Z |
| format | Article |
| id | doaj.art-e7356c87b1ac4158ab76e05d89db7a45 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T01:45:35Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-e7356c87b1ac4158ab76e05d89db7a452023-11-18T16:18:33ZengMDPI AGCells2073-44092023-06-011213168310.3390/cells12131683Evaluation of Homogentisic Acid, a Prospective Antibacterial Agent Highlighted by the Suitability of Nitisinone in Alkaptonuria 2 (SONIA 2) Clinical TrialNicola Ooi0Ian R. Cooper1Brendan Norman2James A. Gallagher3Nick Sireau4George Bou-Gharios5Lakshminarayan R. Ranganath6Victoria J. Savage7Infex Therapeutics, Alderley Park, Macclesfield SK10 4TG, UKInfex Therapeutics, Alderley Park, Macclesfield SK10 4TG, UKInstitute of Life Course and Medical Sciences, William Henry Duncan Building, University of Liverpool, Liverpool L7 8TX, UKInstitute of Life Course and Medical Sciences, William Henry Duncan Building, University of Liverpool, Liverpool L7 8TX, UKAKU Society, Cambridge CB1 2BL, UKInstitute of Life Course and Medical Sciences, William Henry Duncan Building, University of Liverpool, Liverpool L7 8TX, UKInstitute of Life Course and Medical Sciences, William Henry Duncan Building, University of Liverpool, Liverpool L7 8TX, UKInfex Therapeutics, Alderley Park, Macclesfield SK10 4TG, UKDespite 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.https://www.mdpi.com/2073-4409/12/13/1683alkaptonuriaAKUhomogentisic acidantimicrobialbacteriasafety |
| spellingShingle | Nicola Ooi Ian R. Cooper Brendan Norman James A. Gallagher Nick Sireau George Bou-Gharios Lakshminarayan R. Ranganath Victoria J. Savage Evaluation of Homogentisic Acid, a Prospective Antibacterial Agent Highlighted by the Suitability of Nitisinone in Alkaptonuria 2 (SONIA 2) Clinical Trial Cells alkaptonuria AKU homogentisic acid antimicrobial bacteria safety |
| 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 | alkaptonuria AKU homogentisic acid antimicrobial bacteria safety |
| url | https://www.mdpi.com/2073-4409/12/13/1683 |
| work_keys_str_mv | AT nicolaooi evaluationofhomogentisicacidaprospectiveantibacterialagenthighlightedbythesuitabilityofnitisinoneinalkaptonuria2sonia2clinicaltrial AT ianrcooper evaluationofhomogentisicacidaprospectiveantibacterialagenthighlightedbythesuitabilityofnitisinoneinalkaptonuria2sonia2clinicaltrial AT brendannorman evaluationofhomogentisicacidaprospectiveantibacterialagenthighlightedbythesuitabilityofnitisinoneinalkaptonuria2sonia2clinicaltrial AT jamesagallagher evaluationofhomogentisicacidaprospectiveantibacterialagenthighlightedbythesuitabilityofnitisinoneinalkaptonuria2sonia2clinicaltrial AT nicksireau evaluationofhomogentisicacidaprospectiveantibacterialagenthighlightedbythesuitabilityofnitisinoneinalkaptonuria2sonia2clinicaltrial AT georgebougharios evaluationofhomogentisicacidaprospectiveantibacterialagenthighlightedbythesuitabilityofnitisinoneinalkaptonuria2sonia2clinicaltrial AT lakshminarayanrranganath evaluationofhomogentisicacidaprospectiveantibacterialagenthighlightedbythesuitabilityofnitisinoneinalkaptonuria2sonia2clinicaltrial AT victoriajsavage evaluationofhomogentisicacidaprospectiveantibacterialagenthighlightedbythesuitabilityofnitisinoneinalkaptonuria2sonia2clinicaltrial |