microorganisms Review Type IA Topoisomerases as Targets for Infectious Disease Treatments Ahmed Seddek 1,2 , Thirunavukkarasu Annamalai 1 and Yuk-Ching Tse-Dinh 1,2, *   Citation: Seddek, A.; Annamalai, T.; Tse-Dinh, Y.-C. Type IA Topoisomerases as Targets for Infectious Disease Treatments. Microorganisms 2021, 9, 86. https://doi.org/10.3390/ microorganisms9010086 Received: 15 November 2020 Accepted: 17 December 2020 Published: 1 Jaunary 2021 Publisher’s Note: MDPI stays neu- tral with regard to jurisdictional clai- ms in published maps and institutio- nal affiliations. Copyright: © 2021 by the authors. Li- censee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and con- ditions of the Creative Commons At- tribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, USA; asedd001@fiu.edu (A.S.); athiruna@fiu.edu (T.A.) 2 Biomolecular Sciences Institute, Florida International University, Miami, FL 33199, USA * Correspondence: ytsedinh@fiu.edu; Tel.: +1-305-348-4956 Abstract: Infectious diseases are one of the main causes of death all over the world, with antimi- crobial 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 topoi- somerases 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 repli- cation, 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: topoisomerase; antimicrobial resistance; drug targets 1. Introduction Infectious diseases are diseases where certain microorganisms grow and replicate inside a host, leading to damage or injury to body tissues of the host. Even normal flora can cause diseases to the host if the host is immunocompromised, for instance in cancer and acquired immunodeficiency syndrome (AIDS). Many effective antimicrobial agents have been discovered and marketed so far. However, there has been a constant issue that counteracts the effects of well-established antimicrobial agents, i.e., antimicrobial drug resistance [1–3]. Antimicrobial resistance has been a major global health concern in recent years. Mech- anisms 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]. 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]. The number of deaths attributable to antimicrobial resistance is expected to continue growing, hitting around 10 million cases in 2050 [13]. Worldwide, tuberculosis (TB) is one of the top 10 causes of death. According to the WHO, TB is the leading cause of death from a single infectious agent. TB caused an estimated 1.4 million deaths worldwide in 2019, with an estimated 10.0 million new cases of TB, equivalent to 130 cases per Microorganisms 2021, 9, 86. https://doi.org/10.3390/microorganisms9010086 https://www.mdpi.com/journal/microorganisms