DNA-Dependent Binding of Nargenicin to DnaE1 Inhibits Replication in Mycobacterium tuberculosis .
Melissa D ChengalroyenMandy K MasonAlessandro BorselliniRaffaella TassoniGarth L AbrahamsSasha LynchYong-Mo AhnJon AmblerKatherine YoungBrendan M CrowleyDavid B OlsenDigby Francis WarnerClifton E Barry IiiHelena I M BoshoffMeindert H LamersValerie MizrahiPublished in: ACS infectious diseases (2022)
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.
Keyphrases
- mycobacterium tuberculosis
- dna binding
- circulating tumor
- pulmonary tuberculosis
- cell free
- electron microscopy
- single molecule
- dna damage response
- drug discovery
- staphylococcus aureus
- structural basis
- infectious diseases
- nucleic acid
- single cell
- high resolution
- binding protein
- oxidative stress
- quality improvement
- climate change
- methicillin resistant staphylococcus aureus