Exploitation of Pare Topoisomerase IV as Drug Target for the Treatment of Multidrug-Resistant Bacteria: A Review
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Pharmaceutical Chemistry Journal, Vol. 54, No. 5, August, 2020 (Russian Original Vol. 54, No. 5, May, 2020)
EXPLOITATION OF PARE TOPOISOMERASE IV AS DRUG TARGET FOR THE TREATMENT OF MULTIDRUG-RESISTANT BACTERIA: A REVIEW Vidyasrilekha Yele1 and Afzal Azam Md1,* Original article submitted April 15, 2020. The antibacterial resistance (ABR) is a growing phenomenon and global threat to mankind. To circumvent the ABR, many approaches have been put forth, but none of them meet the pre-requisites associated with the resistance mechanisms. In this review, we focused on the importance of unexploited enzyme, ParE, a topoisomerase responsible for the bacterial survival. The bacterial topoisomerases maintain the topological state of DNA. The gyrases and topoisomerases IV are validated targets for the antibacterial activity. Both these enzymes are structurally similar and possess high degree conservation in the catalytic domain of the N-terminal region, which make them appealing targets for broad spectrum antibacterial activity. Despite being an attractive target for the development of new antibacterials, there are currently no antibiotics targeting gyrases and topoisomerase (topo) IV in the market. Availability of the high-resolution crystal structure data for ParE made it possible to design new classes of antibacterials. Here, we discuss the importance of targeting topo IV enzyme as it is less prone to bacterial resistance which has been disclosed in the literature. Keywords: antibacterials, topoisomerases, ParE, GyrB, antibiotic resistance.
strike of antibacterials on the same active sites results in genetic mutations, which is a primary cause of ABR prevalence. Bacterial DNA gyrase B (GyrB) and ParE enzyme are related to bacterial topoisomerases. These are clinically validated targets that utilize energy through ATP hydrolysis [2]. GyrB and ParE are considered to be exceedingly conserved topoisomerases that play essential roles in replication and transcription of DNA and are appealing targets for antibacterial drug discovery [3, 4]. DNA gyrase is a heterotetramer consisting of two GyrA and GyrB subunits. It utilizes the energy through hydrolysis of ATP to introduce negative supercoils into DNA and stabilizes the super-helical state of the bacterial chromosome [2]. On the other hand, topoisomerase (topo) IV, a related homolog of gyrase, is a heterotetramer consisting of two ParC and two ParE subunits. It is involved in the process of decatenation required for the separation of daughter chromatids behind the replication fork and after replication of DNA. The N-terminal domain (64 kDa) of GyrA and ParC subunits of topoisomerase provides the active-site tyrosine residue that irreversibly attaches to the cleaved DNA gate [2]. The C-terminal domain (33 kDa) of both GyrA and ParC differ in the similarity of genomic sequence and also in how they bind to the bacterial genome [5]. GyrB and ParE have
1. INTRODUCTION The rapid evolution of emerging antibacterial resistance (ABR) have pushed the need to explore new and alternative an
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