Recent advances in small molecule LpxC inhibitors against gram-negative bacteria (2014-2024)
Pengpeng Ji1, Meng Ma1, Xiaoyue Geng1
1School of Pharmacy, Shandong Second Medical University, Weifang, Shandong, China.
Abstract:
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.
Insights
Multidrug-resistant Gram-negative bacteria are a global health threat. This review examines small molecule LpxC inhibitors, focusing on structure, function, and toxicity to guide future drug development against these challenging pathogens.
Area of Science:
- Microbiology
- Medicinal Chemistry
- Drug Discovery
Background:
- The World Health Organization (WHO) has identified multidrug-resistant (MDR) Gram-negative bacteria as a critical public health threat.
- These bacteria are responsible for a growing number of difficult-to-treat infections.
- The enzyme Uridine diphosphate-3-O-(hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is essential for Gram-negative bacteria outer membrane synthesis and is a promising drug target.
Purpose of the Study:
- To review recent advancements in the development of small molecule LpxC inhibitors.
- To analyze structure-activity relationships and conformational aspects of LpxC inhibitors.
- To discuss animal toxicity data and its implications for clinical translation.
Main Methods:
- Literature review of small molecule LpxC inhibitors published in the last 10 years, with emphasis on the last 5 years.
- Analysis of structural modifications and their impact on inhibitory activity.
- Evaluation of preclinical safety and toxicity data.
Main Results:
- Numerous small molecule LpxC inhibitors have been synthesized, including notable examples like L-573,655, TU-514, CHIR-090, ACHN-975, and TP0586532.
- Despite promising preclinical data, only ACHN-975 reached Phase I clinical trials before discontinuation due to safety concerns.
- Limited success in clinical trials highlights challenges in LpxC inhibitor development, particularly regarding safety and efficacy.
Conclusions:
- LpxC remains a validated and attractive target for novel antibiotics against MDR Gram-negative bacteria.
- Further research into structure optimization and comprehensive toxicity profiling is crucial for successful clinical development.
- Understanding conformational dynamics and improving safety profiles are key to advancing LpxC inhibitors as viable therapeutic options.
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