scholarly journals Benzamide Derivatives Targeting the Cell Division Protein FtsZ: Modifications of the Linker and the Benzodioxane Scaffold and Their Effects on Antimicrobial Activity

Antibiotics ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 160 ◽  
Author(s):  
Valentina Straniero ◽  
Lorenzo Suigo ◽  
Andrea Casiraghi ◽  
Victor Sebastián-Pérez ◽  
Martina Hrast ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Cell Division ◽  
Single Molecule ◽  
Efflux Pump ◽  
Computational Study ◽  
Structural Features ◽  
Temperature Sensitive ◽  
Bacterial Cell Division ◽  
Gram Positive ◽  
Prokaryotic Protein

Filamentous temperature-sensitive Z (FtsZ) is a prokaryotic protein with an essential role in the bacterial cell division process. It is widely conserved and expressed in both Gram-positive and Gram-negative strains. In the last decade, several research groups have pointed out molecules able to target FtsZ in Staphylococcus aureus, Bacillus subtilis and other Gram-positive strains, with sub-micromolar Minimum Inhibitory Concentrations (MICs). Conversely, no promising derivatives active on Gram-negatives have been found up to now. Here, we report our results on a class of benzamide compounds, which showed comparable inhibitory activities on both S. aureus and Escherichia coli FtsZ, even though they proved to be substrates of E. coli efflux pump AcrAB, thus affecting the antimicrobial activity. These surprising results confirmed how a single molecule can target both species while maintaining potent antimicrobial activity. A further computational study helped us decipher the structural features necessary for broad spectrum activity and assess the drug-like profile and the on-target activity of this family of compounds.

scholarly journals Movement Dynamics of Divisome and Penicillin-Binding Proteins (PBPs) in Cells of Streptococcus pneumoniae

2018 ◽  
Author(s):  
Amilcar J. Perez ◽  
Yann Cesbron ◽  
Sidney L. Shaw ◽  
Jesus Bazan Villicana ◽  
Ho-Ching T. Tsui ◽  
...  
Keyword(s):  
Cell Division ◽  
Streptococcus Pneumoniae ◽  
Single Molecule ◽  
Protein Complexes ◽  
Bacterial Cell Division ◽  
Dynamic Movement ◽  
Movement Dynamics ◽  
Directional Movement ◽  
Tightly Coupled ◽  
Filament Bundles

ABSTRACTBacterial cell division and peptidoglycan (PG) synthesis are orchestrated by the coordinated dynamic movement of essential protein complexes. Recent studies show that bidirectional treadmilling of FtsZ filaments/bundles is tightly coupled to and limiting for both septal PG synthesis and septum closure in some bacteria, but not in others. Here we report the dynamics of FtsZ movement leading to septal and equatorial ring formation in the ovoid-shaped pathogen, Streptococcus pneumoniae (Spn). Conventional and single-molecule total internal reflection fluorescence microscopy (TIRFm) showed that nascent rings of FtsZ and its anchoring and stabilizing proteins FtsA and EzrA move out from mature septal rings coincident with MapZ rings early in cell division. This mode of continuous nascent ring movement contrasts with a failsafe streaming mechanism of FtsZ/FtsA/EzrA observed in a ΔmapZ mutant and another Streptococcus species. This analysis also provides several parameters of FtsZ treadmilling in nascent and mature rings, including treadmilling velocity in wild-type cells and ftsZ(GTPase) mutants, lifetimes of FtsZ subunits in filaments and of entire FtsZ filaments/bundles, and the processivity length of treadmilling of FtsZ filament/bundles. In addition, we delineated the motion of the septal PBP2x transpeptidase and its FtsW glycosyl transferase binding partner relative to FtsZ treadmilling in Spn cells. Five lines of evidence support the conclusion that movement of the bPBP2x:FtsW complex in septa depends on PG synthesis and not on FtsZ treadmilling. Together, these results support a model in which FtsZ dynamics and associations organize and distribute septal PG synthesis, but do not control its rate in Spn.SignificanceThis study answers two long-standing questions about FtsZ dynamics and its relationship to septal PG synthesis in Spn for the first time. In previous models, FtsZ concertedly moves from midcell septa to MapZ rings that have reached the equators of daughter cells. Instead, the results presented here show that FtsZ, FtsA, and EzrA filaments/bundles move continuously out from early septa as part of MapZ rings. In addition, this study establishes that the movement of bPBP2x:FtsW complexes in septal PG synthesis depends on and likely mirrors new PG synthesis and is not correlated with the treadmilling of FtsZ filaments/bundles. These findings are consistent with a mechanism where septal FtsZ rings organize directional movement of bPBP2x:FtsW complexes dependent on PG substrate availability.

scholarly journals Molecular Simplification of Natural Products: Synthesis, Antibacterial Activity, and Molecular Docking Studies of Berberine Open Models

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 452
Author(s):  
Gualtiero Milani ◽  
Maria Maddalena Cavalluzzi ◽  
Roberta Solidoro ◽  
Lara Salvagno ◽  
Laura Quintieri ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Molecular Docking ◽  
Parent Compound ◽  
Biological Properties ◽  
Docking Studies ◽  
Bacterial Cell Division ◽  
Gram Positive ◽  
Test Species ◽  
Gram Negative ◽  
Docking Simulations

Berberine, the main bioactive component of many medicinal plants belonging to various genera such as Berberis, Coptis, and Hydrastis is a multifunctional compound. Among the numerous interesting biological properties of berberine is broad antimicrobial activity including a range of Gram-positive and Gram-negative bacteria. With the aim of identifying berberine analogues possibly endowed with higher lead-likeness and easier synthetic access, the molecular simplification approach was applied to the secondary metabolite and a series of analogues were prepared and screened for their antimicrobial activity against Gram-positive and Gram-negative bacterial test species. Rewardingly, the berberine simplified analogues displayed 2–20-fold higher potency with respect to berberine. Since our berberine simplified analogues may be easily synthesized and are characterized by lower molecular weight than the parent compound, they are further functionalizable and should be more suitable for oral administration. Molecular docking simulations suggested FtsZ, a well-known protein involved in bacterial cell division, as a possible target.

scholarly journals Active Stable Maintenance Functions in Low Copy-Number Plasmids of Gram-positive Bacteria. I. Partition Systems

2013 ◽  
Vol 62 (1) ◽  
pp. 3-16 ◽  
Author(s):  
MICHAŁ DMOWSKI ◽  
GRAŻYNA JAGURA-BURDZY
Keyword(s):  
Cell Division ◽  
Copy Number ◽  
Significant Contribution ◽  
Bacterial Cell Division ◽  
Gram Positive ◽  
Gram Positive Bacteria ◽  
Daughter Cells ◽  
Low Copy Number ◽  
Random Segregation ◽  
Stable Maintenance

Low copy number plasmids cannot rely on the random segregation during bacterial cell division. To be stably maintained in the population they evolved two types of mechanisms (i) partition systems (PAR) that actively separate replicated plasmid molecules to the daughter cells and (ii) toxin-andidote systems (TA) that act after cell division to kill plasmid-less cells. Our knowledge of partition systems has been based mainly on analysis of plasmids from Gram-negative bacteria. Now, numerous partition systems of plasmids from Gram-positive bacteria have also been characterized and make significant contribution to our understanding of these mechanisms.

Cyathin, a new antibiotic complex produced by Cyathus helenae

1971 ◽  
Vol 17 (11) ◽  
pp. 1401-1407 ◽  
Author(s):  
A. D. Allbutt ◽  
W. A. Ayer ◽  
H. J. Brodie ◽  
B. N. Johri ◽  
H. Taube
Keyword(s):  
Antimicrobial Activity ◽  
Liquid Medium ◽  
Room Temperature ◽  
Action Spectrum ◽  
Structural Features ◽  
Gram Positive ◽  
Gram Negative ◽  
Static Culture

The fungus Cyathus helenae Brodie (Gasteromycetes) produces a complex of antibiotic substances collectively called cyathin. Highest yields were obtained when the fungus was grown at room temperature for 25 days on a chemically defined liquid medium in static culture. The action spectrum of cyathin (and its components) was determined by placing cyathin-bearing paper discs on agar plates seeded with the microorganisms being tested. The cyathin complex is active against actinomycetes, bacteria (gram-positive as well as gram-negative), and some fungi, including dermatophytes. Weaker antimicrobial activity is also shown by C. striatus (Huds.) Willd. ex Pers., C. poeppigii L., and C. limbatus L. Seven different compounds have been isolated from the cyathin complex: 2,4,5-trihydroxybenzaldehyde (C7H6O4),cyathin A3(C20H30O3), cyathin A4(C20H30O4),allocyathinA4(C20H30O4),cyathin B3(C20H28O3), cyathin B4(C20H28O4), and cyathin C5(C20H26O5). Aside from 2,4,5-trihydroxybenzaldehyde, these compounds appear not to have been previously described. A discussion of some of the structural features of cyathin A4 and cyathin A3 is presented

scholarly journals ¡vIVA la DivIVA!

2019 ◽  
Vol 201 (21) ◽  
Author(s):  
Lauren R. Hammond ◽  
Maria L. White ◽  
Prahathees J. Eswara
Keyword(s):  
Cell Division ◽  
Chromosome Segregation ◽  
Parental Cell ◽  
Model Organisms ◽  
Posttranslational Regulation ◽  
Bacterial Cell Division ◽  
Gram Positive ◽  
Content Type ◽  
Gram Positive Bacteria ◽  
Division Cell

ABSTRACT Reproduction in the bacterial kingdom predominantly occurs through binary fission—a process in which one parental cell is divided into two similarly sized daughter cells. How cell division, in conjunction with cell elongation and chromosome segregation, is orchestrated by a multitude of proteins has been an active area of research spanning the past few decades. Together, the monumental endeavors of multiple laboratories have identified several cell division and cell shape regulators as well as their underlying regulatory mechanisms in rod-shaped Escherichia coli and Bacillus subtilis, which serve as model organisms for Gram-negative and Gram-positive bacteria, respectively. Yet our understanding of bacterial cell division and morphology regulation is far from complete, especially in noncanonical and non-rod-shaped organisms. In this review, we focus on two proteins that are highly conserved in Gram-positive organisms, DivIVA and its homolog GpsB, and attempt to summarize the recent advances in this area of research and discuss their various roles in cell division, cell growth, and chromosome segregation in addition to their interactome and posttranslational regulation.

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

Antibiotics ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 873
Author(s):  
Wern Chern Chai ◽  
Jonathan J. Whittall ◽  
Di Song ◽  
Steven W. Polyak ◽  
Abiodun D. Ogunniyi ◽  
...  
Keyword(s):  
Cell Division ◽  
Antimicrobial Agents ◽  
Efflux Pump ◽  
Coli Strain ◽  
Haemolytic Activity ◽  
Bacterial Cell Division ◽  
Beta Lactam ◽  
Beta Lactam Antibiotics ◽  
Mrsa Strains ◽  
Ftsz Inhibitors

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.

scholarly journals Movement dynamics of divisome proteins and PBP2x:FtsW in cells of Streptococcus pneumoniae

2019 ◽  
Vol 116 (8) ◽  
pp. 3211-3220 ◽  
Author(s):  
Amilcar J. Perez ◽  
Yann Cesbron ◽  
Sidney L. Shaw ◽  
Jesus Bazan Villicana ◽  
Ho-Ching T. Tsui ◽  
...  
Keyword(s):  
Cell Division ◽  
Streptococcus Pneumoniae ◽  
Single Molecule ◽  
Protein Complexes ◽  
Bacterial Cell Division ◽  
Binding Partner ◽  
Dynamic Movement ◽  
Movement Dynamics ◽  
Tightly Coupled ◽  
Filament Bundles

Bacterial cell division and peptidoglycan (PG) synthesis are orchestrated by the coordinated dynamic movement of essential protein complexes. Recent studies show that bidirectional treadmilling of FtsZ filaments/bundles is tightly coupled to and limiting for both septal PG synthesis and septum closure in some bacteria, but not in others. Here we report the dynamics of FtsZ movement leading to septal and equatorial ring formation in the ovoid-shaped pathogen, Streptococcus pneumoniae. Conventional and single-molecule total internal reflection fluorescence microscopy (TIRFm) showed that nascent rings of FtsZ and its anchoring and stabilizing proteins FtsA and EzrA move out from mature septal rings coincident with MapZ rings early in cell division. This mode of continuous nascent ring movement contrasts with a failsafe streaming mechanism of FtsZ/FtsA/EzrA observed in a ΔmapZ mutant and another Streptococcus species. This analysis also provides several parameters of FtsZ treadmilling in nascent and mature rings, including treadmilling velocity in wild-type cells and ftsZ(GTPase) mutants, lifetimes of FtsZ subunits in filaments and of entire FtsZ filaments/bundles, and the processivity length of treadmilling of FtsZ filament/bundles. In addition, we delineated the motion of the septal PBP2x transpeptidase and its FtsW glycosyl transferase-binding partner relative to FtsZ treadmilling in S. pneumoniae cells. Five lines of evidence support the conclusion that movement of the bPBP2x:FtsW complex in septa depends on PG synthesis and not on FtsZ treadmilling. Together, these results support a model in which FtsZ dynamics and associations organize and distribute septal PG synthesis, but do not control its rate in S. pneumoniae.

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