A Nitroreductase-Activatable Lapachol Against Bacillus subtilis Unveils Antimicrobial Specificity

IF 3.4 4区医学 Q2 CHEMISTRY, MEDICINAL

ChemMedChem Pub Date : 2026-03-13 DOI:10.1002/cmdc.202500997

Ivonne R. Lopez-Miranda, Tianyi Ma, Joshua N. Milstein, Andrew A. Beharry

引用次数: 0

Abstract

Lapachol is a natural product with antimicrobial activity. Though promising for combating antimicrobial resistance, lapachol has toxicity to mammalian cells, which will cause severe side effects in vivo. To mitigate this, we developed alapachol prodrug which is dependent on the action of nitroreductase—an enzyme expressed in bacteria but not healthy mammalian cells. We observed release of lapachol in vitro by purified nitroreductase and in the gram-positive bacterial strain, Bacillus subtilis. Colony formation assays in Bacillus subtilis indicated release of lapachol, achieving comparable levels of toxicity as free lapachol. Lastly, minimal toxicity of our prodrug was observed in mammalian cell culture, demonstrating a >10-fold selectivity for bacteria over healthy mammalian cells.

Abstract Image

查看原文本刊更多论文

一种硝基还原酶激活的抗枯草芽孢杆菌的Lapachol揭示了抗菌特异性。

Lapachol是一种具有抗菌活性的天然产品。虽然在抗微生物药物耐药性方面很有前景，但拉帕恰尔对哺乳动物细胞有毒性，在体内会引起严重的副作用。为了减轻这种情况，我们开发了alapachol前药，它依赖于硝基还原酶的作用——一种在细菌中表达的酶，而不是健康的哺乳动物细胞。我们观察了纯化的硝基还原酶和革兰氏阳性细菌枯草芽孢杆菌在体外释放拉帕恰尔。枯草芽孢杆菌的菌落形成试验表明释放拉帕恰尔，达到与游离拉帕恰尔相当的毒性水平。最后，在哺乳动物细胞培养中观察到我们的前药毒性很小，表明对细菌的选择性是健康哺乳动物细胞的10倍。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

ChemMedChem 医学-药学

CiteScore

6.70

自引率

2.90%

发文量

280

审稿时长

1 months

期刊介绍： Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.