scholarly journals PBP1 of Staphylococcus aureus has multiple essential functions in cell division

2021 ◽  
Author(s):  
Katarzyna Wacnik ◽  
Vincenzo A Rao ◽  
Xinyue Chen ◽  
Lucia Lafage ◽  
Manuel Pazos ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Division ◽  
Bacterial Cell Division ◽  
Penicillin Binding Proteins ◽  
Multiple Components ◽  
Multi Stage ◽  
Complex Process ◽  
Plate Formation ◽  
Major Structural Component ◽  
Division Process

Bacterial cell division is a complex process requiring the coordination of multiple components, to allow the appropriate spatial and temporal control of septum formation and cell scission. Peptidoglycan (PG) is the major structural component of the septum, and our recent studies in the human pathogen Staphylococcus aureus have revealed a complex, multi–stage PG architecture that develops during septation. Penicillin binding proteins (PBPs) are essential for the final steps of PG biosynthesis — their transpeptidase activity links together the peptide sidechain of nascent glycan strands together. PBP1 is required for cell division in S. aureus and here we demonstrate that it has multiple essential functions associated with its enzymatic activity and as a regulator of division. Loss of PBP1, or just its C–terminal PASTA domains, results in cessation of division at the point of septal plate formation. The PASTA domains can bind PG and thus coordinate the cell division process. The transpeptidase activity of PBP1 is also essential but its loss leads to a strikingly different phenotype of thickened and aberrant septa, which is phenocopied by the morphological effects of adding the PBP1–specific β–lactam, meropenem. Together these results lead to a model for septal PG synthesis where PBP1 enzyme activity is responsible for the characteristic architecture of the septum and PBP1 protein molecules coordinate cell division allowing septal plate formation.

scholarly journals Antisense Growth Inhibition of Methicillin-Resistant Staphylococcus aureus by Locked Nucleic Acid Conjugated with Cell-Penetrating Peptide as a Novel FtsZ Inhibitor

2014 ◽  
Vol 59 (2) ◽  
pp. 914-922 ◽  
Author(s):  
Jingru Meng ◽  
Fei Da ◽  
Xue Ma ◽  
Ning Wang ◽  
Yukun Wang ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Division ◽  
Nucleic Acid ◽  
Bacterial Cell ◽  
Locked Nucleic Acid ◽  
Bacterial Cell Division ◽  
Inhibitory Effects ◽  
Content Type ◽  
Division Process

ABSTRACTMethicillin-resistantStaphylococcus aureus(MRSA) infections are becoming increasingly difficult to treat, owing to acquired antibiotic resistance. The emergence and spread of MRSA limit therapeutic options and require new therapeutic strategies, including novel MRSA-active antibiotics. Filamentous temperature-sensitive protein Z (FtsZ) is a highly conserved bacterial tubulin homologue that is essential for controlling the bacterial cell division process in different species ofS. aureus. We conjugated a locked nucleic acid (LNA) that targetedftsZmRNA with the peptide (KFF)3K, to generate peptide-LNA (PLNA). The present study aimed to investigate whether PLNA could be used as a novel antibacterial agent. PLNA787, the most active agent synthesized, exhibited promising inhibitory effects on four pathogenicS. aureusstrainsin vitro. PLNA787 inhibited bacterial growth and resolved lethal Mu50 infections in epithelial cell cultures. PLNA787 also improved the survival rates of Mu50-infected mice and was associated with reductions of bacterial titers in several tissue types. The inhibitory effects onftsZmRNA and FtsZ protein expression and inhibition of the bacterial cell division process are considered to be the major mechanisms of PLNA. PLNA787 demonstrated activity against MRSA infectionsin vitroandin vivo. Our findings suggest thatftsZmRNA is a promising new target for developing novel antisense antibiotics.

scholarly journals Acyldepsipeptide antibiotics – current state of knowledge

2015 ◽  
Vol 64 (2) ◽  
pp. 85-92
Author(s):  
MICHAŁ T. PSTRĄGOWSKI ◽  
MAGDALENA BUJALSKA-ZADROŻNY
Keyword(s):  
Staphylococcus Aureus ◽  
Bacillus Subtilis ◽  
Cell Division ◽  
Streptococcus Pneumoniae ◽  
Animal Studies ◽  
Potential Mechanism ◽  
Bacterial Cell Division ◽  
Resistance Development ◽  
Bacillus Subtilis 168 ◽  
Current State

The objective of this paper is to review and summarize the antimicrobial efficacy of the acyldepsipeptides and to indicate the prospects of the therapeutic values of these compounds. This work is enriched by the description of the mutations within the clpP1clpP2 and c1pP3clpP4 operons of Streptomyces lividans, which are considered to be the potential mechanism of the acyldepsipeptide (ADEP)-resistance development. The researchers' conclusions demonstrated a significant impact on microorganisms including the destabilization of bacterial cell division in Bacillus subtilis 168, Staphylococcus aureus HG001 and Streptococcus pneumoniae G9A strains. The results of animal studies show higher bactericidal effectiveness of the acyldepsipeptides ADEP-2 and ADEP-4 compared to linezolid. ADEPs may be considered as a very important mechanism of defense against the increasing resistance of microorganisms . They also might prevent or reduce the risk of many epidemiological events.

scholarly journals Crystal Structure of a Peptidoglycan Synthesis Regulatory Factor (PBP3) fromStreptococcus pneumoniae

2004 ◽  
Vol 280 (16) ◽  
pp. 15984-15991 ◽  
Author(s):  
Cécile Morlot ◽  
Lucile Pernot ◽  
Audrey Le Gouellec ◽  
Anne Marie Di Guilmi ◽  
Thierry Vernet ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Cell Growth ◽  
Soluble Form ◽  
Bacterial Cell Division ◽  
Efficient Manner ◽  
Penicillin Binding Proteins ◽  
Peptidoglycan Synthesis ◽  
Division Process ◽  
Omega Loop ◽  
Β Sheet

Penicillin-binding proteins (PBPs) are membrane-associated enzymes which perform critical functions in the bacterial cell division process. The singled-Ala,d-Ala (d,d)-carboxypeptidase inStreptococcus pneumoniae, PBP3, has been shown to play a key role in control of availability of the peptidoglycal substrate during cell growth. Here, we have biochemically characterized and solved the crystal structure of a soluble form of PBP3 to 2.8 Å resolution. PBP3 folds into an NH2-terminal,d,d-carboxypeptidase-like domain, and a COOH-terminal, elongated β-rich region. The carboxypeptidase domain harbors the classic signature of the penicilloyl serine transferase superfamily, in that it contains a central, five-stranded antiparallel β-sheet surrounded by α-helices. As in other carboxypeptidases, which are present in species whose peptidoglycan stem peptide has a lysine residue at the third position, PBP3 has a 14-residue insertion at the level of its omega loop, a feature that distinguishes it from carboxypeptidases from bacteria whose peptidoglycan harbors a diaminopimelate moiety at this position. PBP3 performs substrate acylation in a highly efficient manner (kcat/Km= 50,500m–1·s–1), an event that may be linked to role in control of pneumococcal peptidoglycan reticulation. A model that places PBP3 poised vertically on the bacterial membrane suggests that its COOH-terminal region could act as a pedestal, placing the active site in proximity to the peptidoglycan and allowing the protein to “skid” on the surface of the membrane, trimming pentapeptides during the cell growth and division processes.

scholarly journals Antibacterial mechanism of rhodomyrtone involves the disruption of nucleoid segregation checkpoint in Streptococcus suis

2020 ◽  
Author(s):  
Apichaya Traithan ◽  
Pongsri Tongtawe ◽  
Jeeraphong Thanongsaksrikul ◽  
Supayang Voravuthikunchai ◽  
Potjanee Sriman
Keyword(s):  
Cell Division ◽  
Early Stage ◽  
Streptococcus Suis ◽  
Transmission Electron Micrograph ◽  
Antibacterial Mechanism ◽  
Bacterial Cell Division ◽  
Transmission Electron ◽  
Inhibition Concentration ◽  
Division Process ◽  
Z Ring

Abstract Rhodomyrtone has been recently demonstrated to possess a novel antibiotic mechanism of action against Gram-positive bacteria which involves multiple targets, resulting in the interference of several bacterial biological processes including cell division. The present study aims to closely look at the downstream effect of rhodomyrtone treatment on nucleoid segregation in Streptococcus suis, an important zoonotic pathogen. Minimum inhibition concentration (MIC) and minimum bactericidal concentration (MBC) values of rhodomyrtone against recombinant S. suis ParB-GFP, a nucleoid segregation reporter strain, were 0.5 and 1 µg/ml, respectively, equivalent to the potency of vancomycin. Using fluorescence live-cell imaging, we demonstrated that rhodomyrtone at 2 × MIC caused incomplete nucleoid segregation and septum misplacement, leading to the generation of anucleated cells. FtsZ immune-staining of rhodomyrtone-treated S. suis for 30 min revealed that although large amount of FtsZ was trapped in the region of high fluidity membrane, it appeared to be able to polymerize to form a complete Z-ring. However, the Z-ring was shifted away from midcell. Transmission electron micrograph further confirmed disruption of nucleoid segregation and septum misplacement at 120 min following rhodomyrtone treatment. Asymmetric septum formation resulted in either generation of minicells without nucleoid, septum formed over incomplete segregated nucleoid (guillotine effect), or formation of multi-constriction of Z-ring within a single cell. This finding spotlights on antibacterial mechanism of rhodomyrtone involves the early stage in bacterial cell division process.

scholarly journals Structure of the bacterial cell division determinant GpsB and its interaction with penicillin-binding proteins

2015 ◽  
Vol 99 (5) ◽  
pp. 978-998 ◽  
Author(s):  
Jeanine Rismondo ◽  
Robert M. Cleverley ◽  
Harriet V. Lane ◽  
Stephanie Großhennig ◽  
Anne Steglich ◽  
...  
Keyword(s):  
Cell Division ◽  
Bacterial Cell ◽  
Binding Proteins ◽  
Bacterial Cell Division ◽  
Penicillin Binding Proteins

scholarly journals ZapE Is a Novel Cell Division Protein Interacting with FtsZ and Modulating the Z-Ring Dynamics

mBio ◽  
2014 ◽  
Vol 5 (2) ◽  
Author(s):  
Benoit S. Marteyn ◽  
Gouzel Karimova ◽  
Andrew K. Fenton ◽  
Anastasia D. Gazi ◽  
Nicholas West ◽  
...  
Keyword(s):  
Cell Division ◽  
Bacterial Cell ◽  
Dependent Manner ◽  
Bacterial Cell Division ◽  
Low Oxygen ◽  
Ftsz Ring ◽  
Division Process ◽  
Z Ring ◽  
Cell Division Protein

ABSTRACTBacterial cell division requires the formation of a mature divisome complex positioned at the midcell. The localization of the divisome complex is determined by the correct positioning, assembly, and constriction of the FtsZ ring (Z-ring). Z-ring constriction control remains poorly understood and (to some extent) controversial, probably due to the fact that this phenomenon is transient and controlled by numerous factors. Here, we characterize ZapE, a novel ATPase found in Gram-negative bacteria, which is required for growth under conditions of low oxygen, while loss ofzapEresults in temperature-dependent elongation of cell shape. We found that ZapE is recruited to the Z-ring during late stages of the cell division process and correlates with constriction of the Z-ring. Overexpression or inactivation ofzapEleads to elongation ofEscherichia coliand affects the dynamics of the Z-ring during division.In vitro, ZapE destabilizes FtsZ polymers in an ATP-dependent manner.IMPORTANCEBacterial cell division has mainly been characterizedin vitro. In this report, we could identify ZapE as a novel cell division protein which is not essentialin vitrobut is required during an infectious process. The bacterial cell division process relies on the assembly, positioning, and constriction of FtsZ ring (the so-called Z-ring). Among nonessential cell division proteins recently identified, ZapE is the first in which detection at the Z-ring correlates with its constriction. We demonstrate that ZapE abundance has to be tightly regulated to allow cell division to occur; absence or overexpression of ZapE leads to bacterial filamentation. AszapEis not essential, we speculate that additional Z-ring destabilizing proteins transiently recruited during late cell division process might be identified in the future.

scholarly journals Structural analysis of the interaction between the bacterial cell division proteins FtsQ and FtsB

2018 ◽  
Author(s):  
Danguole Kureisaite-Ciziene ◽  
Aravindan Varadajan ◽  
Stephen H. McLaughlin ◽  
Marjolein Glas ◽  
Alejandro Montón Silva ◽  
...  
Keyword(s):  
Cell Division ◽  
Membrane Proteins ◽  
Bacterial Cell ◽  
Outer Membrane Proteins ◽  
Ring Structure ◽  
Globular Domain ◽  
Bacterial Cell Division ◽  
Division Site ◽  
Division Process

AbstractMost bacteria and archaea use similar proteins within their cell division machinery, which uses the tubulin homologue FtsZ as its central organiser. In Gram-negative Escherichia coli bacteria, FtsZ recruits cytosolic, transmembrane, periplasmic and outer membrane proteins, assembling the divisome that facilitates bacterial cell division. One such divisome component, FtsQ, a bitopic membrane protein with a globular domain in the periplasm, has been shown to interact with many other divisome proteins. Despite its otherwise unknown function, it has been shown to be a major divisome interaction hub. Here, we investigated the interactions of FtsQ with FtsB and FtsL, two small bitopic membrane proteins that act immediately downstream of FtsQ. In biochemical assays we show that the periplasmic domains of E. coli FtsB and FtsL interact with FtsQ, but not with each other. Our crystal structure of FtsB bound to the β domain of FtsQ shows that only residues 64-87 of FtsB interact with FtsQ. A synthetic peptide comprising those 24 FtsB residues recapitulates the FtsQ:FtsB interactions. Protein deletions and structure-guided mutant analyses validate the structure. Furthermore, the same structure-guided mutants show cell division defects in vivo that are consistent with our structure of the FtsQ:FtsB complex that shows their interactions as they occur during cell division. Our work provides intricate details of the interactions within the divisome and also provides a tantalising view of a highly conserved protein interaction in the periplasm of bacteria that is an excellent target for cell division inhibitor searches.ImportanceCells in most bacteria and archaea divide through a cell division process that is characterised through its filamentous organiser, FtsZ protein. FtsZ forms a ring structure at the division site and starts the recruitment of 10-20 downstream proteins that together form an elusive multi-protein complex termed divisome. The divisome is thought to facilitate many of the steps required to make two cells out of one. FtsQ and FtsB are part of the divisome, with FtsQ being a central hub, interacting with most of the other divisome components. Here we show for the first time how FtsQ interacts with its downstream partner FtsB and show that mutations that disturb the interface between the two proteins effectively inhibit cell division.

scholarly journals Antibacterial mechanism of rhodomyrtone involves the disruption of nucleoid segregation checkpoint in Streptococcus suis

2020 ◽  
Author(s):  
Apichaya Traithan ◽  
Pongsri Tongtawe ◽  
Jeeraphong Thanongsaksrikul ◽  
Supayang Voravuthikunchai ◽  
Potjanee Sriman
Keyword(s):  
Cell Division ◽  
Early Stage ◽  
Streptococcus Suis ◽  
Antibacterial Mechanism ◽  
Bacterial Cell Division ◽  
Gram Positive Bacteria ◽  
Transmission Electron ◽  
Inhibition Concentration ◽  
Division Process ◽  
Z Ring

Abstract Rhodomyrtone has been recently demonstrated to possess a novel antibiotic mechanism of action against Gram-positive bacteria which involved the multiple targets, resulting in the interference of several bacterial biological processes including the cell division. The present study aims to closely look at the downstream effect of rhodomyrtone treatment on nucleoid segregation in Streptococcus suis, an important zoonotic pathogen. The minimum inhibition concentration (MIC) and the minimum bactericidal concentration (MBC) values of rhodomyrtone against the recombinant S. suis ParB-GFP, a nucleoid segregation reporter strain, were 0.5 and 1 µg/ml, respectively, which were equivalent to the potency of vancomycin. Using the fluorescence live-cell imaging, we demonstrated that rhodomyrtone at 2 × MIC caused incomplete nucleoid segregation and septum misplacement, leading to the generation of anucleated cells. FtsZ immune-staining of rhodomyrtone-treated S. suis for 30 min revealed that the large amount of FtsZ was trapped in the region of high fluidity membrane and appeared to be able to polymerize to form a complete Z-ring. However, the Z-ring was shifted away from the midcell. Transmission electron microscopy further confirmed the disruption of nucleoid segregation and septum misplacement at 120 min following the rhodomyrtone treatment. Asymmetric septum formation resulted in either generation of minicells without nucleoid, septum formed over incomplete segregated nucleoid (guillotine effect), or formation of multi-constriction of Z-ring within a single cell. This finding spotlights on antibacterial mechanism of rhodomyrtone involves the early stage in bacterial cell division process.

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