FtsZ Interactions and Biomolecular Condensates as Potential Targets for New Antibiotics

Zorrilla, Silvia; Monterroso, Begoña; Robles-Ramos, Miguel-Ángel; Margolin, William; Rivas, Germán

doi:10.3390/antibiotics10030254

Cited by 10 publications

(10 citation statements)

References 157 publications

(136 reference statements)

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“…FtsZ is a key factor in the divisome complex and inhibition of its GTPase activity by TL impairs cell division [7]. Nowadays, Ftsz is recognized as a leading target in the search for new antibacterial compounds, since it is an essential protein for cell division in most bacteria and is absent in humans [16]. A large number of FtsZ inhibitors, including peptides, natural products, and other synthetic small molecules, have been proposed which might lead to the discovery of novel FtsZ-targeting clinical drugs [17].…”

Section: Discussionmentioning

confidence: 99%

Interaction of Temporin-L Analogues with the E. coli FtsZ Protein

et al. 2021

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The research of new therapeutic agents to fight bacterial infections has recently focused on the investigation of antimicrobial peptides (AMPs), the most common weapon that all organisms produce to prevent invasion by external pathogens. Among AMPs, the amphibian Temporins constitute a well-known family with high antibacterial properties against Gram-positive and Gram-negative bacteria. In particular, Temporin-L was shown to affect bacterial cell division by inhibiting FtsZ, a tubulin-like protein involved in the crucial step of Z-ring formation at the beginning of the division process. As FtsZ represents a leading target for new antibacterial compounds, in this paper we investigated in detail the interaction of Temporin L with Escherichia coli FtsZ and designed two TL analogues in an attempt to increase peptide-protein interactions and to better understand the structural determinants leading to FtsZ inhibition. The results demonstrated that the TL analogues improved their binding to FtsZ, originating stable protein-peptide complexes. Functional studies showed that both peptides were endowed with a high capability of inhibiting both the enzymatic and polymerization activities of the protein. Moreover, the TL analogues were able to inhibit bacterial growth at low micromolar concentrations. These observations may open up the way to the development of novel peptide or peptidomimetic drugs tailored to bind FtsZ, hampering a crucial process of bacterial life that might be proposed for future pharmaceutical applications.

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Section: Discussionmentioning

confidence: 99%

Interaction of Temporin-L Analogues with the E. coli FtsZ Protein

et al. 2021

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“…The core structure of FtsZ consists of an N-terminal nucleotide-binding domain (NBD) and a C-terminal GTPase activation domain (GAD), joined by the long central helix H7 ( Figure 1 C). A variable unstructured C-terminal linker connects the FtsZ core to a binding motif for several of the FtsZ membrane tethering and partner proteins [ 5 ], whose interactions are also potential antibiotic targets [ 28 ]. FtsZ proteins spontaneously fold without requiring chaperones [ 29 ].…”

Section: Cell Division Protein Ftsz As An Antibacterial Targetmentioning

confidence: 99%

The Search for Antibacterial Inhibitors Targeting Cell Division Protein FtsZ at Its Nucleotide and Allosteric Binding Sites

et al. 2022

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The global spread of bacterial antimicrobial resistance is associated to millions of deaths from bacterial infections per year, many of which were previously treatable. This, combined with slow antibiotic deployment, has created an urgent need for developing new antibiotics. A still clinically unexploited mode of action consists in suppressing bacterial cell division. FtsZ, an assembling GTPase, is the key protein organizing division in most bacteria and an attractive target for antibiotic discovery. Nevertheless, developing effective antibacterial inhibitors targeting FtsZ has proven challenging. Here we review our decade-long multidisciplinary research on small molecule inhibitors of bacterial division, in the context of global efforts to discover FtsZ-targeting antibiotics. We focus on methods to characterize synthetic inhibitors that either replace bound GTP from the FtsZ nucleotide binding pocket conserved across diverse bacteria or selectively bind into the allosteric site at the interdomain cleft of FtsZ from Bacillus subtilis and the pathogen Staphylococcus aureus. These approaches include phenotype screening combined with fluorescence polarization screens for ligands binding into each site, followed by detailed cytological profiling, and biochemical and structural studies. The results are analyzed to design an optimized workflow to identify effective FtsZ inhibitors, and new approaches for the discovery of FtsZ-targeting antibiotics are discussed.

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“…Among the leading strategies for the exploration and detection of new targets in pathogens are the masterfully using bioinformatics tools. These tools can provide useful information for better comprehension of the interactions between targets and biomolecules and therefore help to anticipate new treatment targets for pathogenic microorganisms [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

In-Depth Study of Thymus vulgaris Essential Oil: Towards Understanding the Antibacterial Target Mechanism and Toxicological and Pharmacological Aspects

Akermi

Smaoui

Fourati

et al. 2022

BioMed Research International

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Questions have been raised apropos the emerging problem of microbial resistance, which may pose a great hazard to the human health. Among biosafe compounds are essential oils which captured consumer draw due to their multifunctional properties compared to chemical medication drugs. Here, we examined the chemical profile and the mechanism(s) of action of the Thymus vulgaris essential oil (TVEO) against a Gram-negative bacterium Salmonella enterica Typhimurium ATTCC 10028 (S. enterica Typhimurium ATTCC 10028) and two Gram-positive bacteria Staphyloccocus aureus ATCC 6538 (S. aureus ATCC 6538) and Listeria monocytogenes ATCC 19117 (L. monocytogenes ATCC 19117). Findings showed that TVEO was principally composed of thymol, o-cymene, and γ-terpinene with 47.44, 16.55, and 7.80%, respectively. Molecular docking simulations stipulated that thymol and β-sesquiphellandrene (a minor compound at 1.37%) could target multiple bacterial pathways including topoisomerase II and DNA and RNA polymerases of the three tested bacteria. This result pointed plausible impairments of the pathogenic bacteria cell replication and transcription processes. Through computational approach, the VEGA quantitative structure–activity relationship (QSAR) model, we revealed that among twenty-six TVEO compounds, sixteen had no toxic effects and could be safe for human consumption as compared to the Food and Drug Administration (FDA) approved drugs (ciprofloxacin and rifamycin SV). Assessed by the SwissADME server, the pharmacokinetic profile of all identified TVEO compounds define their absorption, distribution, metabolism, and excretion (ADME) properties and were assessed. In order to predict their biological activity spectrum based on their chemical structure, all TVEO compounds were subjected to PASS (Prediction of Activity Spectra for Substances) online tool. Results indicated that the tested compounds could have multiple biological activities and various enzymatic targets. Findings of our study support that identified compounds of TVEO can be a safe and effective alternative to synthetic drugs and can easily combats hazardous multidrug-resistant bacteria.

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FtsZ Interactions and Biomolecular Condensates as Potential Targets for New Antibiotics

Cited by 10 publications

References 157 publications

Interaction of Temporin-L Analogues with the E. coli FtsZ Protein

Interaction of Temporin-L Analogues with the E. coli FtsZ Protein

The Search for Antibacterial Inhibitors Targeting Cell Division Protein FtsZ at Its Nucleotide and Allosteric Binding Sites

In-Depth Study of Thymus vulgaris Essential Oil: Towards Understanding the Antibacterial Target Mechanism and Toxicological and Pharmacological Aspects

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