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Review
. 2021 Jan 1;9(1):86.
doi: 10.3390/microorganisms9010086.

Type IA Topoisomerases as Targets for Infectious Disease Treatments

Ahmed Seddek  1   2 , Thirunavukkarasu Annamalai  1 , Yuk-Ching Tse-Dinh  1   2
Affiliations
Review

Type IA Topoisomerases as Targets for Infectious Disease Treatments

Ahmed Seddek et al. Microorganisms. .

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.

Keywords: antimicrobial resistance; drug targets; topoisomerase.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
DNA-gate formed by cleavage of G-strand DNA by type IA topoisomerase (A) Crystal structure of covalent complex between single-stranded DNA (ssDNA) and E. coli topoisomerase I N-terminal domains I to IV (Protein Data Bank (PDB) 3PX7). The active tyrosine residue Y319 is illustrated with the red color, and ssDNA is represented by the blue color. (B) Gate opening and closing dynamics of bacterial topoisomerase IA. The enzyme is represented by the green shape and the ssDNA is represented by the blue wavy line. The letter Y stands for the active site tyrosine residue Y319.
Figure 2
Figure 2
Structures of bis-benzimidazoles Hoechst 33258, Hoechst 33342, 2′-(4-ethoxyphenyl)-5-(4-propylpiperazin-1-yl)-1H,1′H-2,5′-bibenzo[d]imidazole (PPEF) and DPA 154.
Figure 3
Figure 3
Structures of tricyclic antidepressant imipramine and metabolite norclomipramine.
Figure 4
Figure 4
(A) Polyamine scaffold and (B) individual polyamine inhibitors of bacterial topoisomerase I with antimycobacterial activity [112].
Figure 5
Figure 5
Gold(III) inhibitors of bacterial topoisomerase I [113]. (A) Gold(III) macrocycle 10 and (B) gold(III) chelate 14.
Figure 6
Figure 6
Structures of fluoroquinophenoxazine 11a and 11g [114].
Figure 7
Figure 7
VCC891909 from Vichem’s Nested Chemical Library (NCL) [98].
Figure 8
Figure 8
Alkaloids seconeolitsine (SCN) and N-methyl seconeolitsine (N-SCN) [136].
Figure 9
Figure 9
Bacterial topoisomerase I inhibitors identified by in silico screening—piperidine amide compound 7 [95] and NSC76027 [94].
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