Abstract

Widespread antimicrobial resistance among bacterial pathogens is a serious threat to public health. Thus, identification of new targets and development of new antibacterial agents are urgently needed. Although cell division is a major driver of bacterial colonization and pathogenesis, its targeting with antibacterial compounds is still in its infancy. FtsZ, a bacterial cytoskeletal homolog of eukaryotic tubulin, plays a highly conserved and foundational role in cell division and has been the primary focus of research on small molecule cell division inhibitors. FtsZ contains two drug-binding pockets: the GTP binding site situated at the interface between polymeric subunits, and the inter-domain cleft (IDC), located between the N-terminal and C-terminal segments of the core globular domain of FtsZ. The majority of anti-FtsZ molecules bind to the IDC. Compounds that bind instead to the GTP binding site are much less useful as potential antimicrobial therapeutics because they are often cytotoxic to mammalian cells, due to the high sequence similarity between the GTP binding sites of FtsZ and tubulin. Fortunately, the IDC has much less sequence and structural similarity with tubulin, making it a better potential target for drugs that are less toxic to humans. Over the last decade, a large number of natural and synthetic IDC inhibitors have been identified. Here we outline the molecular structure of IDC in detail and discuss how it has become a crucial target for broad spectrum and species-specific antibacterial agents. We also outline the drugs that bind to the IDC and their modes of action.

Highlights

  • The battle against infectious diseases has been a persistent challenge for humans

  • Division of bacterial cells is key for their colonization and pathogenesis, the cell division machinery has not been fully explored for the development of antibacterial agents despite many breakthroughs in the mechanisms and regulation of this fundamental process

  • We have described many small molecules that can interact with the inter-domain cleft (IDC) of FtsZ

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Summary

Introduction

The battle against infectious diseases has been a persistent challenge for humans. The development and use of antibiotics helped to prevent and control bacterial infections, but at the same time its misuse led to the development of antibacterial resistance (Ma and Ma, 2012). The second major binding site in FtsZ that interacts with small molecules is the IDC, formed by the C-terminal half of the H7 helix, the T7 loop and the beta sheets in the C-terminal domain (Figure 1C) (Sun et al, 2014). The drugs that bind to the IDC in FtsZ do not interact with tubulin with similar affinity and are less likely to be toxic to mammalian cells.

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