Mechanistic Studies of the Calcium-Dependent Antibiotics via Cofactor Engineering
Journal
Journal of Natural Products
Journal Volume
89
Journal Issue
2
Start Page
639
End Page
644
ISSN
0163-3864
1520-6025
Date Issued
2026-01-15
Author(s)
Abstract
The defining feature of calcium-dependent antibiotics (CDAs) is that they require the presence of calcium cation (Ca(II)) as a cofactor to exert antibacterial activity. We recently showed that substituting two key aspartic acids (Asp) with serine (Ser) in laspartomycin C (LspC) converts it from a CDA into a boron-dependent antibiotic (BDA). This synthetic analog (termed B1) no longer depends on Ca(II) and requires only 10 μM of phenylboronic acid (PBA) to become fully active. Such a calcium-to-boron dependence conversion provides a new entry point to study the mechanistic details of the cofactor dependence of CDAs, a rare phenomenon among bioactive small molecules. Herein, we show that electron withdrawing substituents on PBA enhance the antibacterial activity of B1. The friulimicin and daptomycin synthetic analogs with the same Asp-to-Ser substitution were inactive, whereas the CDA4b synthetic analog exhibited dual cofactor dependence. CDA4b was fully activated when both Ca(II) and PBA were present and was 4-fold less potent in the presence of only one or the other. These findings suggest that not only do CDAs often have distinct cellular targets, the way they are activated by Ca(II) are also different. Such mechanistic diversity underscores the strong potential of CDAs in drug development.
Publisher
American Chemical Society (ACS)
Type
journal article