For information about COVID-19, including symptoms and prevention, please read our COVID-19 patient guide. Please also consider supporting Weill Cornell Medicine’s efforts against the pandemic.
Microbiology and Immunology

You are here

Derivatives of Natural Product Agrimophol as Disruptors of Intrabacterial pH Homeostasis in .

TitleDerivatives of Natural Product Agrimophol as Disruptors of Intrabacterial pH Homeostasis in .
Publication TypeJournal Article
Year of Publication2019
AuthorsWu J, Mu R, Sun M, Zhao N, Pan M, Li H, Dong Y, Sun Z, Bai J, Hu M, Nathan C, Javid B, Liu G
JournalACS Infect Dis
Volume5
Issue7
Pagination1087-1104
Date Published2019 Jul 12
ISSN2373-8227
Abstract

This article reports the rational medicinal chemistry of a natural product, agrimophol (), as a new disruptor of intrabacterial pH (pH) homeostasis in (). Through the systematic investigation of the structure-activity relationship of , scaffold-hopping of the diphenylmethane scaffold, pharmacophore displacement strategies, and studies of the structure-metabolism relationship, a new derivative was achieved. Compound showed 100-fold increased potency in the ability to reduce pH to pH 6.0 and similarly improved mycobactericidal activity compared with against both -BCG and . Compound possessed improved metabolic stability in human liver microsomes and hepatocytes, lower cytotoxicity, higher selectivity index, and similar p value to natural . This study introduces a novel scaffold to an old drug, resulting in improved mycobactericidal activity through decreasing pH, and may contribute to the critical search for new agents to overcome drug resistance and persistence in the treatment of tuberculosis.

DOI10.1021/acsinfecdis.8b00325
Alternate JournalACS Infect Dis
PubMed ID31016962

Weill Cornell Medicine Microbiology and Immunology 1300 York Avenue, Box 62 New York, NY 10065 Phone: (212) 746-6505 Fax: (212) 746-8587