Recent advances in small molecule LpxC inhibitors against gram-negative bacteria (2014–2024)
In 2024, WHO added multiple multidrug-resistant (MDR) Gram-negative bacteria to the bacteria priority pathogens list, and the continued increase in MDR Gram-negative bacteria poses a serious threat to public health. Uridine diphosphate-3-O-(hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is...
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmicb.2025.1541379/full |
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| author | Pengpeng Ji Meng Ma Xiaoyue Geng Jian Zhang |
| author_facet | Pengpeng Ji Meng Ma Xiaoyue Geng Jian Zhang |
| author_sort | Pengpeng Ji |
| collection | DOAJ |
| description | In 2024, WHO added multiple multidrug-resistant (MDR) Gram-negative bacteria to the bacteria priority pathogens list, and the continued increase in MDR Gram-negative bacteria poses a serious threat to public health. Uridine diphosphate-3-O-(hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a metalloenzyme cofactored with zinc ions, which is a key enzyme in the synthesis of outer membrane lipid A in Gram negative bacteria. LpxC is highly conserved and homologous among different Gram-negative bacteria, which makes LpxC a promising target against multidrug-resistant Gram-negative bacteria. Since the first report of the arazoline LpxC inhibitor L-573, 655, a large number of small molecule LpxC inhibitors against Gram-negative bacteria have been synthesized and tested, such as TU-514, CHIR-090, ACHN-975 and TP0586532. However, only ACHN-975 entered clinical phase I trials and was discontinued due to safety concerns, so far none of the LpxC inhibitors are available. This paper mainly focuses on the structure optimization, conformational relationship and animal toxicity of small molecule LpxC inhibitors over the past 10 years, especially in the last 5 years, in order to provide ideas for the development and clinical research of LpxC inhibitors. |
| format | Article |
| id | doaj-art-9a9446a0cdc94a7eb94faf9c167d2b0d |
| institution | Kabale University |
| issn | 1664-302X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj-art-9a9446a0cdc94a7eb94faf9c167d2b0d2025-02-10T06:48:53ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2025-02-011610.3389/fmicb.2025.15413791541379Recent advances in small molecule LpxC inhibitors against gram-negative bacteria (2014–2024)Pengpeng JiMeng MaXiaoyue GengJian ZhangIn 2024, WHO added multiple multidrug-resistant (MDR) Gram-negative bacteria to the bacteria priority pathogens list, and the continued increase in MDR Gram-negative bacteria poses a serious threat to public health. Uridine diphosphate-3-O-(hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a metalloenzyme cofactored with zinc ions, which is a key enzyme in the synthesis of outer membrane lipid A in Gram negative bacteria. LpxC is highly conserved and homologous among different Gram-negative bacteria, which makes LpxC a promising target against multidrug-resistant Gram-negative bacteria. Since the first report of the arazoline LpxC inhibitor L-573, 655, a large number of small molecule LpxC inhibitors against Gram-negative bacteria have been synthesized and tested, such as TU-514, CHIR-090, ACHN-975 and TP0586532. However, only ACHN-975 entered clinical phase I trials and was discontinued due to safety concerns, so far none of the LpxC inhibitors are available. This paper mainly focuses on the structure optimization, conformational relationship and animal toxicity of small molecule LpxC inhibitors over the past 10 years, especially in the last 5 years, in order to provide ideas for the development and clinical research of LpxC inhibitors.https://www.frontiersin.org/articles/10.3389/fmicb.2025.1541379/fullLpxC inhibitorsgram-negative bacteriamultidrug-resistant (MDR)CHIR-090TP 0586532 |
| spellingShingle | Pengpeng Ji Meng Ma Xiaoyue Geng Jian Zhang Recent advances in small molecule LpxC inhibitors against gram-negative bacteria (2014–2024) Frontiers in Microbiology LpxC inhibitors gram-negative bacteria multidrug-resistant (MDR) CHIR-090 TP 0586532 |
| title | Recent advances in small molecule LpxC inhibitors against gram-negative bacteria (2014–2024) |
| title_full | Recent advances in small molecule LpxC inhibitors against gram-negative bacteria (2014–2024) |
| title_fullStr | Recent advances in small molecule LpxC inhibitors against gram-negative bacteria (2014–2024) |
| title_full_unstemmed | Recent advances in small molecule LpxC inhibitors against gram-negative bacteria (2014–2024) |
| title_short | Recent advances in small molecule LpxC inhibitors against gram-negative bacteria (2014–2024) |
| title_sort | recent advances in small molecule lpxc inhibitors against gram negative bacteria 2014 2024 |
| topic | LpxC inhibitors gram-negative bacteria multidrug-resistant (MDR) CHIR-090 TP 0586532 |
| url | https://www.frontiersin.org/articles/10.3389/fmicb.2025.1541379/full |
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