Topoisomerases: Resistance versus Sensitivity, How Far We Can Go?
DNA topoisomerases are ubiquitously present remarkable molecular machines that help in altering topology of DNA in living cells. The crucial role played by these nucleases during DNA replication, transcription, and recombination vis-à-vis less sequence similarity among different species makes topoisomerases unique and attractive targets for different anticancer and antibacterial drugs. However, druggability of topoisomerases by the existing class of molecules is increasingly becoming questationable due to resistance development predominated by mutations in the corresponding genes. The current scenario facing a decline in the development of new molecules further comprises an important factor that may challenge topoisomerase-targeting therapy. Thus, it is imperative to wisely use the existing inhibitors lest with this rapid rate of losing grip over the target we may not go too far. Furthermore, it is important not only to design new molecules but also to develop new approaches that may avoid obstacles in therapies due to multiple resistance mechanisms. This review provides a succinct account of different classes of topoisomerase inhibitors, focuses on resistance acquired by mutations in topoisomerases, and discusses the various approaches to increase the efficacy of topoisomerase inhibitors. In a later section, we also suggest the possibility of using bisbenzimidazoles along with efflux pump inhibitors for synergistic bactericidal effects.
Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, New Delhi, India.
Sandhya
S
Bansal
Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India.
Priyanka
P
Bajaj
Department of Chemistry, University of Delhi, New Delhi, India.
Stuti
S
Pandey
Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India.|Department of Chemistry, University of Delhi, New Delhi, India.
Vibha
V
Tandon
D026942:DNA Topoisomerases / Q000737:chemistry / Q000378:metabolism*; D004351:Drug Resistance; D006801:Humans; D059003:Topoisomerase Inhibitors / Q000494:pharmacology*
D059003:Topoisomerase Inhibitors; D026942:DNA Topoisomerases
antibacterial; anticancer; efflux pumps; mutations; topoisomerase