scholarly journals EssH Peptidoglycan Hydrolase EnablesStaphylococcus aureusType VII Secretion across the Bacterial Cell Wall Envelope

2018 ◽  
Vol 200 (20) ◽  
Author(s):  
Maksym Bobrovskyy ◽  
Stephanie E. Willing ◽  
Olaf Schneewind ◽  
Dominique Missiakas
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Bacterial Cell ◽  
Bacterial Cell Wall ◽  
Hydrolase Activity ◽  
Amide Bond ◽  
Peptidoglycan Hydrolase ◽  
Bacterial Membrane ◽  
Secretion Systems ◽  
Content Type

ABSTRACTThe ESAT-6-like secretion system (ESS) ofStaphylococcus aureusis assembled in the bacterial membrane from core components that promote the secretion of WXG-like proteins (EsxA, EsxB, EsxC, and EsxD) and the EssD effector. Genes encoding the ESS secretion machinery components, effector, and WXG-like proteins are located in theesslocus. Here, we identifyessH, a heretofore uncharacterized gene of theesslocus, whose product is secreted via an N-terminal signal peptide into the extracellular medium of staphylococcal cultures. EssH exhibits two peptidoglycan hydrolase activities, cleaving the pentaglycine cross bridge and the amide bond ofN-acetylmuramyl-l-alanine, thereby separating glycan chains and wall peptides with cleaved cross bridges. Unlike other peptidoglycan hydrolases, EssH does not promote the lysis of staphylococci. EssH residues Cys199and His254, which are conserved in other CHAP domain enzymes, are required for peptidoglycan hydrolase activity and forS. aureusESS secretion. These data suggest that EssH and its murein hydrolase activity are required for protein secretion by the ESS pathway.IMPORTANCEGene clusters encoding WXG-like proteins and FtsK/SpoIIIE-like P loop ATPases inFirmicutesencode type 7b secretion systems (T7bSS) for the transport of select protein substrates. TheStaphylococcus aureusT7bSS assembles in the bacterial membrane and promotes the secretion of WXG-like proteins and effectors. The mechanisms whereby staphylococci extend the T7SS across the bacterial cell wall envelope are not known. Here, we show that staphylococci secrete EssH to cleave their peptidoglycan, thereby enabling T7bSS transport of proteins across the bacterial cell wall envelope.

scholarly journals Rhodomyrtone Accumulates in Bacterial Cell Wall and Cell Membrane and Inhibits the Synthesis of Multiple Cellular Macromolecules in Epidemic Methicillin-Resistant Staphylococcus aureus

Antibiotics ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 543
Author(s):  
Ozioma F. Nwabor ◽  
Sukanlaya Leejae ◽  
Supayang P. Voravuthikunchai
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Cell Membrane ◽  
Bacterial Cell ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Treatment Options ◽  
Bacterial Cell Wall ◽  
Methicillin Resistant ◽  
Gram Positive Bacteria ◽  
Inhibitor Compounds

As the burden of antibacterial resistance worsens and treatment options become narrower, rhodomyrtone—a novel natural antibiotic agent with a new antibacterial mechanism—could replace existing antibiotics for the treatment of infections caused by multi-drug resistant Gram-positive bacteria. In this study, rhodomyrtone was detected within the cell by means of an easy an inexpensive method. The antibacterial effects of rhodomyrtone were investigated on epidemic methicillin-resistant Staphylococcus aureus. Thin-layer chromatography demonstrated the entrapment and accumulation of rhodomyrtone within the bacterial cell wall and cell membrane. The incorporation of radiolabelled precursors revealed that rhodomyrtone inhibited the synthesis of macromolecules including DNA, RNA, proteins, the cell wall, and lipids. Following the treatment with rhodomyrtone at MIC (0.5–1 µg/mL), the synthesis of all macromolecules was significantly inhibited (p ≤ 0.05) after 4 h. Inhibition of macromolecule synthesis was demonstrated after 30 min at a higher concentration of rhodomyrtone (4× MIC), comparable to standard inhibitor compounds. In contrast, rhodomyrtone did not affect lipase activity in staphylococci—both epidemic methicillin-resistant S. aureus and S. aureus ATCC 29213. Interfering with the synthesis of multiple macromolecules is thought to be one of the antibacterial mechanisms of rhodomyrtone.

Influence of Carbohydrate Residues on Antibacterial Activity of Vancomycin

2020 ◽  
Vol 17 (4) ◽  
pp. 287-293
Author(s):  
Justyna Samaszko-Fiertek ◽  
Monika Szulc ◽  
Barbara Dmochowska ◽  
Maciej Jaśkiewicz ◽  
Wojciech Kamysz ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Antibacterial Activity ◽  
Bacterial Cell ◽  
Bacterial Cell Wall ◽  
Reductive Alkylation ◽  
Cell Wall Peptidoglycan ◽  
Mechanism Of Interaction ◽  
Reference Strains

This paper presents synthesis of vancomycin derivatives modified with selected 1- and 2-aminoalditols to carboxylic function and 2,5-anhydro-D-mannose and D-talose to amino function of vancosamine via reductive alkylation. MIC and MBC of these derivatives were determined for reference strains of bacteria: Staphylococcus aureus ATCC 25923, ATCC 6538, ATCC 6538/P, S. epidemidis ATCC 14490, E. faecium PCM 1859, E. faecalis PCM 2673, S. pyogenes PCM 465, and S. pneumonia ATCC 49619 and compared with the activity of vancomycin and its aglycone. Our findings confirm that sugar fragments can play an important role in the mechanism of interaction of vancomycin with bacterial cell wall peptidoglycan.

scholarly journals Structure of Pneumococcal Peptidoglycan Hydrolase LytB Reveals Insights into the Bacterial Cell Wall Remodeling and Pathogenesis

2014 ◽  
Vol 289 (34) ◽  
pp. 23403-23416 ◽  
Author(s):  
Xiao-Hui Bai ◽  
Hui-Jie Chen ◽  
Yong-Liang Jiang ◽  
Zhensong Wen ◽  
Yubin Huang ◽  
...  
Keyword(s):  
Cell Wall ◽  
Bacterial Cell ◽  
Bacterial Cell Wall ◽  
Peptidoglycan Hydrolase ◽  
Cell Wall Remodeling

scholarly journals The Killing Mechanism of Teixobactin against Methicillin-Resistant Staphylococcus aureus: an Untargeted Metabolomics Study

mSystems ◽  
2020 ◽  
Vol 5 (3) ◽  
Author(s):  
Maytham Hussein ◽  
John A. Karas ◽  
Elena K. Schneider-Futschik ◽  
Fan Chen ◽  
James Swarbrick ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Membrane Lipids ◽  
Cell Envelope ◽  
Teichoic Acid ◽  
Bacterial Membrane ◽  
Gram Positive ◽  
Methicillin Resistant ◽  
Content Type ◽  
Metabolomics Study

ABSTRACT Antibiotics have served humankind through their use in modern medicine as effective treatments for otherwise fatal bacterial infections. Teixobactin is a first member of newly discovered natural antibiotics that was recently identified from a hitherto-unculturable soil bacterium, Eleftheria terrae, and recognized as a potent antibacterial agent against various Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci. The most distinctive characteristic of teixobactin as an effective antibiotic is that teixobactin resistance could not be evolved in a laboratory setting. It is purported that teixobactin’s “resistance-resistant” mechanism of action includes binding to the essential bacterial cell wall synthesis building blocks lipid II and lipid III. In the present study, metabolomics was used to investigate the potential metabolic pathways involved in the mechanisms of antibacterial activity of the synthetic teixobactin analogue Leu10-teixobactin against a MRSA strain, S. aureus ATCC 700699. The metabolomes of S. aureus ATCC 700699 cells 1, 3, and 6 h following treatment with Leu10-teixobactin (0.5 μg/ml, i.e., 0.5× MIC) were compared to those of the untreated controls. Leu10-teixobactin significantly perturbed bacterial membrane lipids (glycerophospholipids and fatty acids), peptidoglycan (lipid I and II) metabolism, and cell wall teichoic acid (lipid III) biosynthesis as early as after 1 h of treatment, reflecting an initial activity on the cell envelope. Concordant with its time-dependent antibacterial killing action, Leu10-teixobactin caused more perturbations in the levels of key intermediates in pathways of amino-sugar and nucleotide-sugar metabolism and their downstream peptidoglycan and teichoic acid biosynthesis at 3 and 6 h. Significant perturbations in arginine metabolism and the interrelated tricarboxylic acid cycle, histidine metabolism, pantothenate, and coenzyme A biosynthesis were also observed at 3 and 6 h. To conclude, this is the first study to provide novel metabolomics mechanistic information, which lends support to the development of teixobactin as an antibacterial drug for the treatment of multidrug-resistant Gram-positive infections. IMPORTANCE Antimicrobial resistance is one of the greatest threats to the global health system. It is imperative that new anti-infective therapeutics be developed against problematic “superbugs.” The cyclic depsipeptide teixobactin holds much promise as a new class of antibiotics for highly resistant Gram-positive pathogens (e.g., methicillin-resistant Staphylococcus aureus [MRSA]). Understanding its molecular mechanism(s) of action could lead to the design of new compounds with a broader activity spectrum. Here, we describe the first metabolomics study to investigate the killing mechanism(s) of teixobactin against MRSA. Our findings revealed that teixobactin significantly disorganized the bacterial cell envelope, as reflected by a profound perturbation in the bacterial membrane lipids and cell wall biosynthesis (peptidoglycan and teichoic acid). Importantly, teixobactin significantly suppressed the main intermediate d-alanyl-d-lactate involved in the mechanism of vancomycin resistance in S. aureus. These novel results help explain the unique mechanism of action of teixobactin and its lack of cross-resistance with vancomycin.

scholarly journals A Secreted NlpC/P60 Endopeptidase from Photobacterium damselae subsp. piscicida Cleaves the Peptidoglycan of Potentially Competing Bacteria

mSphere ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Johnny Lisboa ◽  
Cassilda Pereira ◽  
Aline Rifflet ◽  
Juan Ayala ◽  
Mateus S. Terceti ◽  
...  
Keyword(s):  
Cell Wall ◽  
Marine Fish ◽  
High Mortality ◽  
Bacterial Cell ◽  
Structural Integrity ◽  
Cell Envelope ◽  
Bacterial Cell Wall ◽  
Gram Negative ◽  
Content Type ◽  
Photobacterium Damselae

ABSTRACT Peptidoglycan (PG) is a major component of the bacterial cell wall, forming a mesh-like structure enwrapping the bacteria that is essential for maintaining structural integrity and providing support for anchoring other components of the cell envelope. PG biogenesis is highly dynamic and requires multiple enzymes, including several hydrolases that cleave glycosidic or amide bonds in the PG. This work describes the structural and functional characterization of an NlpC/P60-containing peptidase from Photobacterium damselae subsp. piscicida (Phdp), a Gram-negative bacterium that causes high mortality of warm-water marine fish with great impact for the aquaculture industry. PnpA (Photobacterium NlpC-like protein A) has a four-domain structure with a hydrophobic and narrow access to the catalytic center and specificity for the γ-d-glutamyl-meso-diaminopimelic acid bond. However, PnpA does not cleave the PG of Phdp or PG of several Gram-negative and Gram-positive bacterial species. Interestingly, it is secreted by the Phdp type II secretion system and degrades the PG of Vibrio anguillarum and Vibrio vulnificus. This suggests that PnpA is used by Phdp to gain an advantage over bacteria that compete for the same resources or to obtain nutrients in nutrient-scarce environments. Comparison of the muropeptide composition of PG susceptible and resistant to the catalytic activity of PnpA showed that the global content of muropeptides is similar, suggesting that susceptibility to PnpA is determined by the three-dimensional organization of the muropeptides in the PG. IMPORTANCE Peptidoglycan (PG) is a major component of the bacterial cell wall formed by long chains of two alternating sugars interconnected by short peptides, generating a mesh-like structure that enwraps the bacterial cell. Although PG provides structural integrity and support for anchoring other components of the cell envelope, it is constantly being remodeled through the action of specific enzymes that cleave or join its components. Here, it is shown that Photobacterium damselae subsp. piscicida, a bacterium that causes high mortality in warm-water marine fish, produces PnpA, an enzyme that is secreted into the environment and is able to cleave the PG of potentially competing bacteria, either to gain a competitive advantage and/or to obtain nutrients. The specificity of PnpA for the PG of some bacteria and its inability to cleave others may be explained by differences in the structure of the PG mesh and not by different muropeptide composition.

Bacterial cell wall-expressed protein A triggers supraclonal B-cell responses upon in vivo infection with Staphylococcus aureus

2005 ◽  
Vol 7 (15) ◽  
pp. 1501-1511 ◽  
Author(s):  
Niklas Palmqvist ◽  
Gregg J. Silverman ◽  
Elisabet Josefsson ◽  
Andrzej Tarkowski
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
B Cell ◽  
Bacterial Cell ◽  
Protein A ◽  
Bacterial Cell Wall ◽  
Cell Responses ◽  
B Cell Responses

scholarly journals Nanoscale Cell Wall Deformation Impacts Long-Range Bacterial Adhesion Forces on Surfaces

2013 ◽  
Vol 80 (2) ◽  
pp. 637-643 ◽  
Author(s):  
Yun Chen ◽  
Akshay K. Harapanahalli ◽  
Henk J. Busscher ◽  
Willem Norde ◽  
Henny C. van der Mei
Keyword(s):  
Cell Wall ◽  
Long Range ◽  
Bacterial Adhesion ◽  
Bacterial Cell ◽  
Adhesion Force ◽  
Bacterial Cell Wall ◽  
Nanomechanical Property ◽  
Adhesion Forces ◽  
Bacterial Strains ◽  
Content Type

ABSTRACTAdhesion of bacteria occurs on virtually all natural and synthetic surfaces and is crucial for their survival. Once they are adhering, bacteria start growing and form a biofilm, in which they are protected against environmental attacks. Bacterial adhesion to surfaces is mediated by a combination of different short- and long-range forces. Here we present a new atomic force microscopy (AFM)-based method to derive long-range bacterial adhesion forces from the dependence of bacterial adhesion forces on the loading force, as applied during the use of AFM. The long-range adhesion forces of wild-typeStaphylococcus aureusparent strains (0.5 and 0.8 nN) amounted to only one-third of these forces measured for their more deformable isogenic Δpbp4mutants that were deficient in peptidoglycan cross-linking. The measured long-range Lifshitz-Van der Waals adhesion forces matched those calculated from published Hamaker constants, provided that a 40% ellipsoidal deformation of the bacterial cell wall was assumed for the Δpbp4mutants. Direct imaging of adhering staphylococci using the AFM peak force-quantitative nanomechanical property mapping imaging mode confirmed a height reduction due to deformation in the Δpbp4mutants of 100 to 200 nm. Across naturally occurring bacterial strains, long-range forces do not vary to the extent observed here for the Δpbp4mutants. Importantly, however, extrapolating from the results of this study, it can be concluded that long-range bacterial adhesion forces are determined not only by the composition and structure of the bacterial cell surface but also by a hitherto neglected, small deformation of the bacterial cell wall, facilitating an increase in contact area and, therewith, in adhesion force.

scholarly journals Demonstration of the role of cell wall homeostasis in Staphylococcus aureus growth and the action of bactericidal antibiotics

2021 ◽  
Vol 118 (44) ◽  
pp. e2106022118
Author(s):  
Bartłomiej Salamaga ◽  
Lingyuan Kong ◽  
Laia Pasquina-Lemonche ◽  
Lucia Lafage ◽  
Milena von und zur Muhlen ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Turgor Pressure ◽  
Regulatory System ◽  
Bactericidal Effect ◽  
Hydrolase Activity ◽  
Peptidoglycan Hydrolase ◽  
Peptidoglycan Synthesis ◽  
Peptidoglycan Hydrolases ◽  
The Face

Bacterial cell wall peptidoglycan is essential, maintaining both cellular integrity and morphology, in the face of internal turgor pressure. Peptidoglycan synthesis is important, as it is targeted by cell wall antibiotics, including methicillin and vancomycin. Here, we have used the major human pathogen Staphylococcus aureus to elucidate both the cell wall dynamic processes essential for growth (life) and the bactericidal effects of cell wall antibiotics (death) based on the principle of coordinated peptidoglycan synthesis and hydrolysis. The death of S. aureus due to depletion of the essential, two-component and positive regulatory system for peptidoglycan hydrolase activity (WalKR) is prevented by addition of otherwise bactericidal cell wall antibiotics, resulting in stasis. In contrast, cell wall antibiotics kill via the activity of peptidoglycan hydrolases in the absence of concomitant synthesis. Both methicillin and vancomycin treatment lead to the appearance of perforating holes throughout the cell wall due to peptidoglycan hydrolases. Methicillin alone also results in plasmolysis and misshapen septa with the involvement of the major peptidoglycan hydrolase Atl, a process that is inhibited by vancomycin. The bactericidal effect of vancomycin involves the peptidoglycan hydrolase SagB. In the presence of cell wall antibiotics, the inhibition of peptidoglycan hydrolase activity using the inhibitor complestatin results in reduced killing, while, conversely, the deregulation of hydrolase activity via loss of wall teichoic acids increases the death rate. For S. aureus, the independent regulation of cell wall synthesis and hydrolysis can lead to cell growth, death, or stasis, with implications for the development of new control regimes for this important pathogen.

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