DNA-Dependent Binding of Nargenicin to DnaE1 Inhibits Replication in Mycobacterium tuberculosis

Natural products
provide a rich source of potential antimicrobials
for treating infectious diseases for which drug resistance has emerged.
Foremost among these diseases is tuberculosis. Assessment of the antimycobacterial
activity of nargenicin, a natural product that targets the replicative
DNA polymerase of Staphylococcus aureus, revealed that it is a bactericidal genotoxin that induces a DNA
damage response in Mycobacterium tuberculosis (Mtb) and inhibits growth by blocking the replicative
DNA polymerase, DnaE1. Cryo-electron microscopy revealed that binding
of nargenicin to Mtb DnaE1 requires the DNA substrate
such that nargenicin is wedged between the terminal base pair and
the polymerase and occupies the position of both the incoming nucleotide
and templating base. Comparative analysis across three bacterial species
suggests that the activity of nargenicin is partly attributable to
the DNA binding affinity of the replicative polymerase. This work
has laid the foundation for target-led drug discovery efforts focused
on Mtb DnaE1.