Drug Candidate Discovery: Targeting Bacterial Topoisomerase I Enzymes for Novel Antibiotic Leads Dissertation

(2017). Drug Candidate Discovery: Targeting Bacterial Topoisomerase I Enzymes for Novel Antibiotic Leads . 10.25148/etd.FIDC004005

thesis or dissertation chair


  • Sandhaus, Shayna


  • Multi-drug resistance in bacterial pathogens has become a global health crisis. Each year, millions of people worldwide are infected with bacterial strains that are resistant to currently available antibiotics. Diseases such as tuberculosis, pneumonia, and gonorrhea have become increasingly more difficult to treat. It is essential that novel drugs and cellular targets be identified in order to treat this resistance. Bacterial topoisomerase IA is a novel drug target that is essential for cellular growth. As it has never been targeted by existing antibiotics, it is an attractive target. Topoisomerase IA is responsible for relieving torsional strain on DNA by relaxing supercoiled DNA following processes such as replication and transcription. The aim of this study is to find novel compounds that can be developed as leads for antibiotics targeting bacterial type IA topoisomerase. Various approaches were used in order to screen thousands of compounds against bacterial type IA topoisomerases, including mixture-based screening and virtual screening. In the mixture-based screen, scaffold mixtures were tested against the M. tuberculosis topoisomerase I enzyme and subsequently optimized for maximum potency and selectivity. The optimized compounds were effective at inhibiting the enzyme at low micromolar concentrations, as well as killing the tuberculosis bacteria. In a virtual screen, libraries with hundreds of thousands of compounds were screened against the E. coli and M. tuberculosis topoisomerase I crystal structures in order to find new classes of drugs. The top hits were effective at inhibiting the enzymes, as well as preventing the growth of M. smegmatis cells in the presence of efflux pump inhibitors. Organometallic complexes containing Cu(II) or Co(III) were tested as well against various topoisomerases in order to determine their selectivity. We discovered a poison for human type II topoisomerase that has utility as an anticancer agent, as it killed even very resistant cell lines of breast and colon cancer. The Co(III) complexes were found to inhibit the bacterial topoisomerase I very selectively over other topoisomerases. The various methods of drug discovery utilized here have been successful at identifying new classes of compounds that may be further developed into antibiotic drugs that specifically target bacterial type IA topoisomerases.

publication date

  • November 14, 2017


  • antibiotic resistance
  • drug discovery
  • topoisomerase

Digital Object Identifier (DOI)