Analysis of FtsZ Crystal Structures Towards a New Target for Antibiotics

Kusuma, Kennardy D.; Griffith, Renate; Harry, Elizabeth J.; Bottomley, Amy L.; Ung, Alison T.

doi:10.1071/ch18347

Cited by 9 publications

(21 citation statements)

References 29 publications

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“…The site shows only a relatively limited conservation across FtsZs of different bacterial species. As a result, variations in the amino-acidic composition and site accessibility could account, at least in part, for the observed differences in the susceptibility Antibiotics 2020, 9, 69 4 of 28 of FtsZ from different bacterial strains to the same inhibitor or to inhibitors belonging to similar chemotypes [11]. While this variability may pose a challenge for the development of broad-spectrum antimicrobials, the specificity of this area and its structural divergence from the corresponding portions of tubulin may rule out potential toxicity concerns of inhibitors targeting the GTP-binding site, which shows a high homology between the two proteins.…”

Section: Interdomain Sitementioning

confidence: 99%

“…The 2,6-difluoro substitution was proven to increase activity. The benzamide group interacts via hydrogen bonds with specific residues in the T7 loop of FtsZ (e.g., Val207 and Leu209 in S. aureus) which are conserved across different species [11]; • An alkylenoxy or alkylenamine linker region of different lengths; • A variable terminal region including either an alkyl chain (functionalized or non-functionalized) or a heterocyclic moiety, which is accommodated in a narrow, deep, and hydrophobic cavity inside the interdomain cleft. In general, affinity is promoted by the possibility to form additional interactions and is strongly limited by the hydrophobic nature and steric constraints of the binding site.…”

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confidence: 99%

“…The relevance of steric hindrance and binding site accessibility across species was further supported by the in silico comparison of FtsZ from different microorganisms. Kusuma et al [11] reported that, in the context of a general conservation of FtsZ across species, staphylococcal FtsZs show closer homology among each other compared to FtsZs from other species. One key difference lies in the degree of curvature of the H7 helix, which in turn determines the size and shape of the binding cleft and, more specifically, the size of the cleft opening, which is significantly larger in Staphylococcii compared to B. subtilis, M. tuberculosis, Aquifex Aeolicus, and P. aeruginosa.…”

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confidence: 99%

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Targeting Bacterial Cell Division: A Binding Site-Centered Approach to the Most Promising Inhibitors of the Essential Protein FtsZ

et al. 2020

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Binary fission is the most common mode of bacterial cell division and is mediated by a multiprotein complex denominated the divisome. The constriction of the Z-ring splits the mother bacterial cell into two daughter cells of the same size. The Z-ring is formed by the polymerization of FtsZ, a bacterial protein homologue of eukaryotic tubulin, and it represents the first step of bacterial cytokinesis. The high grade of conservation of FtsZ in most prokaryotic organisms and its relevance in orchestrating the whole division system make this protein a fascinating target in antibiotic research. Indeed, FtsZ inhibition results in the complete blockage of the division system and, consequently, in a bacteriostatic or a bactericidal effect. Since many papers and reviews already discussed the physiology of FtsZ and its auxiliary proteins, as well as the molecular mechanisms in which they are involved, here, we focus on the discussion of the most compelling FtsZ inhibitors, classified by their main protein binding sites and following a medicinal chemistry approach.

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Section: Interdomain Sitementioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Targeting Bacterial Cell Division: A Binding Site-Centered Approach to the Most Promising Inhibitors of the Essential Protein FtsZ

et al. 2020

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“…Although FtsZ has minimal sequence similarity with tubulin, there are several regions that are highly similar in both proteins. Tubulin and FtsZ share only ∼10–18% sequence identity, yet both exhibit structural homology ( de Pereda et al, 1996 ; Kusuma et al, 2019 ), suggesting convergent evolution ( van den Ent et al, 2001 ; Battaje and Panda, 2017 ). Sequence alignment of FtsZ, α-tubulin and β-tubulin demonstrated that the T1 loop (common glycine), T4 loop (with the tubulin signature motif), T5 loop (common prolines), T6 loop (common asparagine), and T7 loop (common asparagine and aspartate) show high sequence identity.…”

Section: Similarities and Differences Between Tubulin And Ftszmentioning

confidence: 99%

Targeting the Achilles Heel of FtsZ: The Interdomain Cleft

Pradhan

Margolin²,

Beuria

2021

Front. Microbiol.

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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.

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“…This allows for FtsZ inhibitors with selective activity against bacterial cell division. One major structural difference is an interdomain cleft adjacent the H7-core helix that separates the two subdomains of FtsZ, a feature which is not present in tubulin [10]. Additionally, the linker that follows the C-terminal globular domain of FtsZ (also known as the disordered region) is thought to play a role in tethering and maintenance of protein-protein interactions that are essential for bacterial cell division [4].…”

Section: Introductionmentioning

confidence: 99%

Antimicrobial Action and Reversal of Resistance in MRSA by Difluorobenzamide Derivatives Targeted at FtsZ

et al. 2020

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The bacterial cell division protein, FtsZ, has been identified as a target for antimicrobial development. Derivatives of 3-methoxybenzamide have shown promising activities as FtsZ inhibitors in Gram-positive bacteria. We sought to characterise the activity of five difluorobenzamide derivatives with non-heterocyclic substituents attached through the 3-oxygen. These compounds exhibited antimicrobial activity against methicillin resistant Staphylococcus aureus (MRSA), with an isopentyloxy-substituted compound showing modest activity against vancomycin resistant Enterococcus faecium (VRE). The compounds were able to reverse resistance to oxacillin in highly resistant clinical MRSA strains at concentrations far below their MICs. Three of the compounds inhibited an Escherichia coli strain lacking the AcrAB components of a drug efflux pump, which suggests the lack of Gram-negative activity can partly be attributed to efflux. The compounds inhibited cell division by targeting S. aureus FtsZ, producing a dose-dependent increase in GTPase rate which increased the rate of FtsZ polymerization and stabilized the FtsZ polymers. These compounds did not affect the polymerization of mammalian tubulin and did not display haemolytic activity or cytotoxicity. These derivatives are therefore promising compounds for further development as antimicrobial agents or as resistance breakers to re-sensitive MRSA to beta-lactam antibiotics.

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Analysis of FtsZ Crystal Structures Towards a New Target for Antibiotics

Cited by 9 publications

References 29 publications

Targeting Bacterial Cell Division: A Binding Site-Centered Approach to the Most Promising Inhibitors of the Essential Protein FtsZ

Targeting Bacterial Cell Division: A Binding Site-Centered Approach to the Most Promising Inhibitors of the Essential Protein FtsZ

Targeting the Achilles Heel of FtsZ: The Interdomain Cleft

Antimicrobial Action and Reversal of Resistance in MRSA by Difluorobenzamide Derivatives Targeted at FtsZ

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