Type IA Topoisomerases as Targets for Infectious Disease Treatments

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.

What is a supercoiling-sensitive gene? Insights from topoisomerase I inhibition in the Gram-negative bacterium Dickeya dadantii

“…The authors of the latter study analysed the kinetics of SC homeostasis, with a strong initial SC increase followed by a partial relaxation. However, it must be noted that the observed rapid response of the topA gene in both species contradicts the behaviour expected based on that mechanism, since, in analogy to the homeostatic activation of the gyrA/B genes by gyrase inhibition (4), we would have expected an activation in the synthesis of TopoI (24). This repression also contrasts with the activation of topA observed in E. coli after an increase in negative SC induced by oxolinic acid (44), but those experiments were carried in a gyrase mutant strain where the basal SC level is likely more relaxed than in the wild-type strain.…”

“…However, the steady-state SC level of these strains differs from that of wild-type ones, and the associated transcriptomic response was never monitored. In wild-type cells, TopoI seemed a particularly suitable drug target (24), both in clinical research as it is the only enzyme of type IA topoisomerases family in many pathogenic species, but also as a way to study the effect of SC in transcriptional regulation, since this enzyme plays a direct role in the handling of torsional stress associated with transcription, while TopoIV is predominantly involved in replication (25). Additionally, not only was TopoI the first topoisomerase to be discovered (26), but the reduction or loss of its activity due to mutations in the topA gene in E. coli and S. enterica played an important role in the early discovery of the reciprocal interaction between transcription and SC (21,(27)(28)(29).…”

“…Additionally, not only was TopoI the first topoisomerase to be discovered (26), but the reduction or loss of its activity due to mutations in the topA gene in E. coli and S. enterica played an important role in the early discovery of the reciprocal interaction between transcription and SC (21,(27)(28)(29). In recent years, many compounds were shown to act as TopoI inhibitors with unequal effectiveness as antimicrobial agents (24). In particular, one of them named seconeolitsine ( 30) is effective against the Gram-positive bacterium Streptococcus pneumoniae, and at low concentrations, induces a transient SC increase associated with a global change in the transcriptional landscape (31).…”

“…In its catalytic cycle, topoI binds a stretch of single-stranded DNA, cleaves it and undergoes a conformational change to an open conformation, allowing the complementary DNA strand to pass the gate, followed by the religation of the DNA backbone with a gain of one linking number (31)(32)(33)(34). In recent years, many compounds were shown to act as topoI inhibitors with unequal effectiveness as antimicrobial agents (24). In particular, one of them named seconeolitsine was shown to be effective against Streptococcus pneumoniae and Mycobacterium tuberculosis topoI, presumably by interacting with its nucleotide binding site, preventing the topoI conformational change and thus inhibiting DNA binding (34).…”

A Novel Prognostic Biomarker with Potential of High Diagnostic Accuracy in Pulmonary Tuberculosis: An in silico Study

“…reported the TOP3A gene duplication in TB infection. 62 K. Wu et al, through their bioinformatics studies, suggested the involvement of the TOP3A gene in myocardial infarction. 63 Since some studies confirmed the role of the TOP3A gene in TB and hence it might serve as a marker for TB.…”