Antitumor Activity of Lankacidin Group Antibiotics Is Due to Microtubule Stabilization via a Paclitaxel-like Mechanism

Lankacidin
group antibiotics show strong antimicrobial activity
against various Gram-positive bacteria. In addition, they were shown
to have considerable antitumor activity against certain cell line
models. For decades, the antitumor activity of lankacidin was associated
with the mechanism of its antimicrobial action, which is interference
with peptide bond formation during protein synthesis. This, however,
was never confirmed experimentally. Due to significant similarity
to paclitaxel-like hits in a previous computational virtual screening
study, we suggested that the cytotoxic effect of lankacidin is due
to a paclitaxel-like action. In this study, we tested this hypothesis
computationally and experimentally and confirmed that lankacidin is
a microtubule stabilizer that enhances tubulin assembly and displaces
taxoids from their binding site. This study serves as a starting point
for optimization of lankacidin derivatives for better antitumor activities.
It also highlights the power of computational predictions and their
aid in guiding experiments and formulating rigorous hypotheses.