Abstract
Infectious diseases are one of the main causes of death all over the world, with antimicrobial resistance presenting a great challenge. New antibiotics need to be developed to provide therapeutic treatment options, requiring novel drug targets to be identified and pursued. DNA topoisomerases control the topology of DNA via DNA cleavage–rejoining coupled to DNA strand passage. The change in DNA topological features must be controlled in vital processes including DNA replication, transcription, and DNA repair. Type IIA topoisomerases are well established targets for antibiotics. In this review, type IA topoisomerases in bacteria are discussed as potential targets for new antibiotics. In certain bacterial pathogens, topoisomerase I is the only type IA topoisomerase present, which makes it a valuable antibiotic target. This review will summarize recent attempts that have been made to identify inhibitors of bacterial topoisomerase I as potential leads for antibiotics and use of these inhibitors as molecular probes in cellular studies. Crystal structures of inhibitor–enzyme complexes and more in-depth knowledge of their mechanisms of actions will help to establish the structure–activity relationship of potential drug leads and develop potent and selective therapeutics that can aid in combating the drug resistant bacterial infections that threaten public health.
Highlights
Infectious diseases are diseases where certain microorganisms grow and replicate inside a host, leading to damage or injury to body tissues of the host
Resistance to antimicrobial agents is usually genetically encoded by the microorganism, either on the bacterial chromosome, or on a plasmid that can be spread among different strains of microorganisms, resulting in the emergence of new resistant strains [11,12]
Topoisomerase I and topoisomerase III are type IA topoisomerases that are present in bacteria, with reverse gyrase being found in thermophilic bacteria
Summary
Infectious diseases are diseases where certain microorganisms grow and replicate inside a host, leading to damage or injury to body tissues of the host. Mechanisms of resistance vary [4,5], such as degrading or changing the drug molecule to an inactive form inside the microorganism [6], modifying or protecting the target for the antimicrobial agent by the microorganism [7,8], or pumping out the drug molecules from the microorganism cell, known as efflux [9,10]. According to the WHO, TB is the leading cause of death from a single infectious agent. Many efforts have been exerted so far to either synthesize new molecules, or discover new bioactive molecules, which could potentially inhibit specific members of the DNA topoisomerase family, to provide new treatment for cancer and infectious diseases
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