FtsZ and RnpA as Valid Targets while Developing Novel Antimicrobials

A special issue of Antibiotics (ISSN 2079-6382).

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 20385

Special Issue Editor


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Guest Editor
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Luigi Mangiagalli, 25, 20133 Milan, Italy
Interests: drug discovery; medicinal chemistry, structure activity relationship; development of novel antimicrobials; FtsZ inhibitors; RnpA inhibitors; inhibition of bacterial cellular division process
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Special Issue Information

Dear Colleagues,

Antimicrobial resistance is a serious and actual problem for public health. Investigating innovative antibacterial targets could be a favorable way to counteract this issue.

In order to approach this topic, in the last decade two important proteins have started being considered and exploited, due to their crucial role in bacterial viability and to their established druggability: FtsZ and RnpA.

Both FtsZ and RnpA are widely conserved among the highest priority pathogens and have limited to null homology with eukaryotic proteins, hoping for broad-spectrum antimicrobials with low cytotoxicity on human cells.

Starting from these considerations, this Special Issue would invite all researchers involved in fighting antimicrobial resistance by studying FtsZ and RnpA with different perspectives and positions. All manuscripts dealing with the design, synthesis, and the biological evaluation of novel antimicrobials targeting FtsZ and RnpA are welcome, as well as papers developing computational models, innovative assays, target-ligand characterization, crystallographic structures and biological mechanisms related to these two proteins.

I hope for extensive contributions from all over the world, in order to strongly sensitize on this urgent healthcare concern.

Dr. Valentina Straniero
Guest Editor

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Keywords

  • FtsZ inhibitors
  • RnpA inhibition
  • bacteriostatic effect
  • bactericidal effect
  • bacterial cell division process
  • mRNA turnover
  • bacterial virulence factors
  • antimicrobials

Published Papers (7 papers)

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Research

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19 pages, 5623 KiB  
Article
Computational Design and Development of Benzodioxane-Benzamides as Potent Inhibitors of FtsZ by Exploring the Hydrophobic Subpocket
by Valentina Straniero, Victor Sebastián-Pérez, Lorenzo Suigo, William Margolin, Andrea Casiraghi, Martina Hrast, Carlo Zanotto, Irena Zdovc, Antonia Radaelli and Ermanno Valoti
Antibiotics 2021, 10(4), 442; https://doi.org/10.3390/antibiotics10040442 - 15 Apr 2021
Cited by 11 | Viewed by 2347
Abstract
Multidrug resistant Staphylococcus aureus is a severe threat, responsible for most of the nosocomial infections globally. This resistant strain is associated with a 64% increase in death compared to the antibiotic-susceptible strain. The prokaryotic protein FtsZ and the cell division cycle have been [...] Read more.
Multidrug resistant Staphylococcus aureus is a severe threat, responsible for most of the nosocomial infections globally. This resistant strain is associated with a 64% increase in death compared to the antibiotic-susceptible strain. The prokaryotic protein FtsZ and the cell division cycle have been validated as potential targets to exploit in the general battle against antibiotic resistance. Despite the discovery and development of several anti-FtsZ compounds, no FtsZ inhibitors are currently used in therapy. This work further develops benzodioxane-benzamide FtsZ inhibitors. We seek to find more potent compounds using computational studies, with encouraging predicted drug-like profiles. We report the synthesis and the characterization of novel promising derivatives that exhibit very low MICs towards both methicillin-susceptible and -resistant S. aureus, as well as another Gram positive species, Bacillus subtilis, while possessing good predicted physical-chemical properties in terms of solubility, permeability, and chemical and physical stability. In addition, we demonstrate by fluorescence microscopy that Z ring formation and FtsZ localization are strongly perturbed by our derivatives, thus validating the target. Full article
(This article belongs to the Special Issue FtsZ and RnpA as Valid Targets while Developing Novel Antimicrobials)
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22 pages, 5070 KiB  
Article
Staphylococcus aureus RnpA Inhibitors: Computational-Guided Design, Synthesis and Initial Biological Evaluation
by Lorenzo Suigo, Michaelle Chojnacki, Carlo Zanotto, Victor Sebastián-Pérez, Carlo De Giuli Morghen, Andrea Casiraghi, Paul M. Dunman, Ermanno Valoti and Valentina Straniero
Antibiotics 2021, 10(4), 438; https://doi.org/10.3390/antibiotics10040438 - 14 Apr 2021
Cited by 1 | Viewed by 2029
Abstract
Antibiotic resistance is spreading worldwide and it has become one of the most important issues in modern medicine. In this context, the bacterial RNA degradation and processing machinery are essential processes for bacterial viability that may be exploited for antimicrobial therapy. In Staphylococcus [...] Read more.
Antibiotic resistance is spreading worldwide and it has become one of the most important issues in modern medicine. In this context, the bacterial RNA degradation and processing machinery are essential processes for bacterial viability that may be exploited for antimicrobial therapy. In Staphylococcus aureus, RnpA has been hypothesized to be one of the main players in these mechanisms. S. aureus RnpA is able to modulate mRNA degradation and complex with a ribozyme (rnpB), facilitating ptRNA maturation. Corresponding small molecule screening campaigns have recently identified a few classes of RnpA inhibitors, and their structure activity relationship (SAR) has only been partially explored. Accordingly, in the present work, using computational modeling of S. aureus RnpA we identified putative crucial interactions of known RnpA inhibitors, and we used this information to design, synthesize, and biologically assess new potential RnpA inhibitors. The present results may be beneficial for the overall knowledge about RnpA inhibitors belonging to both RNPA2000-like thiosemicarbazides and JC-like piperidine carboxamides molecular classes. We evaluated the importance of the different key moieties, such as the dichlorophenyl and the piperidine of JC2, and the semithiocarbazide, the furan, and the i-propylphenyl ring of RNPA2000. Our efforts could provide a foundation for further computational-guided investigations. Full article
(This article belongs to the Special Issue FtsZ and RnpA as Valid Targets while Developing Novel Antimicrobials)
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17 pages, 1726 KiB  
Article
Optimization of 2-Acylaminocycloalkylthiophene Derivatives for Activity against Staphylococcus aureus RnpA
by Michaelle Chojnacki, Xufeng Cao, Daniel P. Flaherty and Paul M. Dunman
Antibiotics 2021, 10(4), 369; https://doi.org/10.3390/antibiotics10040369 - 31 Mar 2021
Cited by 2 | Viewed by 2215
Abstract
Staphylococcus aureus is well-recognized to cause debilitating bacterial infections that are difficult to treat due to the emergence of antibiotic resistance. As such, there is a need to develop new antimicrobials for the therapeutic intervention of S. aureus disease. To that end, S. [...] Read more.
Staphylococcus aureus is well-recognized to cause debilitating bacterial infections that are difficult to treat due to the emergence of antibiotic resistance. As such, there is a need to develop new antimicrobials for the therapeutic intervention of S. aureus disease. To that end, S. aureus RnpA is an essential enzyme that is hypothesized to participate in two required cellular processes, precursor tRNA (ptRNA) maturation and mRNA degradation. Corresponding high throughput screening campaigns have identified the phenylcarbamoyl cyclic thiopenes as a chemical class of RnpA inhibitors that display promising antibacterial effects by reducing RnpA ptRNA and mRNA degradation activities and low human cell toxicity. Herein, we perform a structure activity relationship study of the chemical scaffold. Results revealed that the cycloalkane ring size and trifluoroacetamide moiety are required for antibacterial activity, whereas modifications of the para and/or meta positions of the pharmacophore’s phenyl group allowed tuning of the scaffold’s antimicrobial performance and RnpA inhibitory activity. The top performing compounds with respect to antimicrobial activity also did not exhibit cytotoxicity to human cell lines at concentrations up to 100 µM, greater than 100-fold the minimum inhibitory concentration (MIC). Focused studies of one analog, RNP0012, which exhibited the most potent antimicrobial and inhibition of cellular RnpA activities revealed that the compound reduced bacterial burden in a murine model of S. aureus disease. Taken together, the results presented are expected to provide an early framework for optimization of next-generation of RnpA inhibitor analogues that may represent progenitors of a new class of antimicrobials. Full article
(This article belongs to the Special Issue FtsZ and RnpA as Valid Targets while Developing Novel Antimicrobials)
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22 pages, 7020 KiB  
Article
Antimicrobial Action and Reversal of Resistance in MRSA by Difluorobenzamide Derivatives Targeted at FtsZ
by Wern Chern Chai, Jonathan J. Whittall, Di Song, Steven W. Polyak, Abiodun D. Ogunniyi, Yinhu Wang, Fangchao Bi, Shutao Ma, Susan J. Semple and Henrietta Venter
Antibiotics 2020, 9(12), 873; https://doi.org/10.3390/antibiotics9120873 - 5 Dec 2020
Cited by 11 | Viewed by 3008
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue FtsZ and RnpA as Valid Targets while Developing Novel Antimicrobials)
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15 pages, 3361 KiB  
Article
Proposal of Potent Inhibitors for a Bacterial Cell Division Protein FtsZ: Molecular Simulations Based on Molecular Docking and ab Initio Molecular Orbital Calculations
by Shohei Yamamoto, Ryosuke Saito, Shunya Nakamura, Haruki Sogawa, Pavel Karpov, Sergey Shulga, Yaroslav Blume and Noriyuki Kurita
Antibiotics 2020, 9(12), 846; https://doi.org/10.3390/antibiotics9120846 - 26 Nov 2020
Cited by 3 | Viewed by 2192
Abstract
The inhibition of a bacterial cell division protein, filamentous temperature-sensitive Z (FtsZ), prevents the reproduction of Mycobacteria. To propose potent inhibitors of FtsZ, the binding properties of FtsZ with various derivatives of Zantrin ZZ3 were investigated at an electronic level, using molecular [...] Read more.
The inhibition of a bacterial cell division protein, filamentous temperature-sensitive Z (FtsZ), prevents the reproduction of Mycobacteria. To propose potent inhibitors of FtsZ, the binding properties of FtsZ with various derivatives of Zantrin ZZ3 were investigated at an electronic level, using molecular simulations. We here employed protein–ligand docking, classical molecular mechanics (MM) optimizations, and ab initio fragment molecular orbital (FMO) calculations. Based on the specific interactions between FtsZ and the derivatives, as determined by FMO calculations, we proposed novel ligands, which can strongly bind to FtsZ and inhibit its aggregations. The introduction of a hydroxyl group into ZZ3 was found to enhance its binding affinity to FtsZ. Full article
(This article belongs to the Special Issue FtsZ and RnpA as Valid Targets while Developing Novel Antimicrobials)
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21 pages, 2250 KiB  
Article
Molecular Characterization of the Burkholderia cenocepacia dcw Operon and FtsZ Interactors as New Targets for Novel Antimicrobial Design
by Gabriele Trespidi, Viola Camilla Scoffone, Giulia Barbieri, Giovanna Riccardi, Edda De Rossi and Silvia Buroni
Antibiotics 2020, 9(12), 841; https://doi.org/10.3390/antibiotics9120841 - 24 Nov 2020
Cited by 8 | Viewed by 2377
Abstract
The worldwide spread of antimicrobial resistance highlights the need of new druggable cellular targets. The increasing knowledge of bacterial cell division suggested the potentiality of this pathway as a pool of alternative drug targets, mainly based on the essentiality of these proteins, as [...] Read more.
The worldwide spread of antimicrobial resistance highlights the need of new druggable cellular targets. The increasing knowledge of bacterial cell division suggested the potentiality of this pathway as a pool of alternative drug targets, mainly based on the essentiality of these proteins, as well as on the divergence from their eukaryotic counterparts. People suffering from cystic fibrosis are particularly challenged by the lack of antibiotic alternatives. Among the opportunistic pathogens that colonize the lungs of these patients, Burkholderia cenocepacia is a well-known multi-drug resistant bacterium, particularly difficult to treat. Here we describe the organization of its division cell wall (dcw) cluster: we found that 15 genes of the dcw operon can be transcribed as a polycistronic mRNA from mraZ to ftsZ and that its transcription is under the control of a strong promoter regulated by MraZ. B. cenocepacia J2315 FtsZ was also shown to interact with the other components of the divisome machinery, with a few differences respect to other bacteria, such as the direct interaction with FtsQ. Using an in vitro sedimentation assay, we validated the role of SulA as FtsZ inhibitor, and the roles of FtsA and ZipA as tethers of FtsZ polymers. Together our results pave the way for future antimicrobial design based on the divisome as pool of antibiotic cellular targets. Full article
(This article belongs to the Special Issue FtsZ and RnpA as Valid Targets while Developing Novel Antimicrobials)
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Review

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21 pages, 3871 KiB  
Review
FtsZ Interactions and Biomolecular Condensates as Potential Targets for New Antibiotics
by Silvia Zorrilla, Begoña Monterroso, Miguel-Ángel Robles-Ramos, William Margolin and Germán Rivas
Antibiotics 2021, 10(3), 254; https://doi.org/10.3390/antibiotics10030254 - 4 Mar 2021
Cited by 7 | Viewed by 5130
Abstract
FtsZ is an essential and central protein for cell division in most bacteria. Because of its ability to organize into dynamic polymers at the cell membrane and recruit other protein partners to form a “divisome”, FtsZ is a leading target in the quest [...] Read more.
FtsZ is an essential and central protein for cell division in most bacteria. Because of its ability to organize into dynamic polymers at the cell membrane and recruit other protein partners to form a “divisome”, FtsZ is a leading target in the quest for new antibacterial compounds. Strategies to potentially arrest the essential and tightly regulated cell division process include perturbing FtsZ’s ability to interact with itself and other divisome proteins. Here, we discuss the available methodologies to screen for and characterize those interactions. In addition to assays that measure protein-ligand interactions in solution, we also discuss the use of minimal membrane systems and cell-like compartments to better approximate the native bacterial cell environment and hence provide a more accurate assessment of a candidate compound’s potential in vivo effect. We particularly focus on ways to measure and inhibit under-explored interactions between FtsZ and partner proteins. Finally, we discuss recent evidence that FtsZ forms biomolecular condensates in vitro, and the potential implications of these assemblies in bacterial resistance to antibiotic treatment. Full article
(This article belongs to the Special Issue FtsZ and RnpA as Valid Targets while Developing Novel Antimicrobials)
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