scholarly journals Parallel evolution of frog antimicrobial peptides produces identical conformations but subtly distinct membrane and antibacterial activities

2018 ◽  
Author(s):  
Giorgia Manzo ◽  
Philip M. Ferguson ◽  
Charlotte Hind ◽  
Melanie Clifford ◽  
V. Benjamin Gustilo ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Rana Temporaria ◽  
Parallel Evolution ◽  
Antibacterial Activities ◽  
Mechanisms Of Action ◽  
Model Membranes ◽  
Dynamic Interactions ◽  
Litoria Aurea ◽  
Α Helix

ABSTRACTFrogs such as Rana temporaria and Litoria aurea secrete numerous closely related antimicrobial peptides (AMPs) as an effective chemical dermal defence. Despite the high similarity in physical properties and preference for adopting secondary amphipathic, α-helix conformations in membrane mimicking milieu, their spectrum of activity and potency often varies considerably. Damage or penetration of the bacterial plasma membrane is considered essential for AMP activity and hence distinguishing apparently similar AMPs according to their behaviour in, and effects on, model membranes will inform understanding of species specific effective antimicrobial mechanisms. Here we use a combination of molecular dynamics simulations, circular dichroism and patch-clamp to investigate the basis for differing anti-bacterial activities in representative AMPs from each species; temporin L and aurein 2.5. Despite adopting near identical, α-helix conformations in the steady-state in a variety of membrane models, these two AMPs can be distinguished both in vitro and in silico based on their dynamic interactions with model membranes; the greater conformational flexibility and the higher amplitude channel conductance induced offers a rationale for the greater potency and broader spectrum of activity of temporin L over aurein 2.5. Specific contributions from individual residues are identified that define the mechanisms of action of each AMP. Our findings suggest AMPs in frogs are examples of parallel evolution whose utility is based on apparently similar but subtly distinct mechanisms of action.

scholarly journals In Vitro Characterization of the Antibacterial Spectrum of Novel Bacterial Type II Topoisomerase Inhibitors of the Aminobenzimidazole Class

2006 ◽  
Vol 50 (4) ◽  
pp. 1228-1237 ◽  
Author(s):  
Nagraj Mani ◽  
Christian H. Gross ◽  
Jonathan D. Parsons ◽  
Brian Hanzelka ◽  
Ute Müh ◽  
...  
Keyword(s):  
Bacterial Resistance ◽  
Wide Spectrum ◽  
Dna Gyrase ◽  
Antibacterial Activities ◽  
Mechanisms Of Action ◽  
Fluoroquinolone Resistance ◽  
Topoisomerase Iv ◽  
Low Frequencies

ABSTRACT Antibiotics with novel mechanisms of action are becoming increasingly important in the battle against bacterial resistance to all currently used classes of antibiotics. Bacterial DNA gyrase and topoisomerase IV (topoIV) are the familiar targets of fluoroquinolone and coumarin antibiotics. Here we present the characterization of two members of a new class of synthetic bacterial topoII ATPase inhibitors: VRT-125853 and VRT-752586. These aminobenzimidazole compounds were potent inhibitors of both DNA gyrase and topoIV and had excellent antibacterial activities against a wide spectrum of problematic pathogens responsible for both nosocomial and community-acquired infections, including staphylococci, streptococci, enterococci, and mycobacteria. Consistent with the novelty of their structures and mechanisms of action, antibacterial potency was unaffected by commonly encountered resistance phenotypes, including fluoroquinolone resistance. In time-kill assays, VRT-125853 and VRT-752586 were bactericidal against Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis, and Haemophilus influenzae, causing 3-log reductions in viable cells within 24 h. Finally, similar to the fluoroquinolones, relatively low frequencies of spontaneous resistance to VRT-125853 and VRT-752586 were found, a property consistent with their in vitro dual-targeting activities.

scholarly journals Identification of Synthetic Host Defense Peptide Mimics That Exert Dual Antimicrobial and Anti-Inflammatory Activities

2012 ◽  
Vol 19 (11) ◽  
pp. 1784-1791 ◽  
Author(s):  
Abhigyan Som ◽  
Nicolás Navasa ◽  
Avital Percher ◽  
Richard W. Scott ◽  
Gregory N. Tew ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Lipoteichoic Acid ◽  
Antibacterial Activities ◽  
Innate Immune Responses ◽  
Content Type ◽  
Host Defense Peptide ◽  
Anti Inflammatory ◽  
Molecular Patterns

ABSTRACTA group of synthetic antimicrobial oligomers, inspired by naturally occurring antimicrobial peptides, were analyzed for the ability to modulate innate immune responses to Toll-like receptor (TLR) ligands. These synthetic mimics of antimicrobial peptides (SMAMPs) specifically reduced cytokine production in response toStaphylococcus aureusand theS. aureuscomponent lipoteichoic acid (LTA), a TLR2 agonist. Anti-inflammatory SMAMPs prevented the induction of tumor necrosis factor (TNF), interleukin 6 (IL-6), and IL-10 in response toS. aureusor LTA, but no other TLR2 ligands. We show that these SMAMPs bind specifically to LTAin vitroand prevent its interaction with TLR2. Importantly, the SMAMP greatly reduced the induction of TNF and IL-6in vivoin mice acutely infected withS. aureuswhile simultaneously reducing bacterial loads dramatically (4 log10). Thus, these SMAMPs can eliminate the damage induced by pathogen-associated molecular patterns (PAMPs) while simultaneously eliminating infectionin vivo. They are the first known SMAMPs to demonstrate anti-inflammatory and antibacterial activitiesin vivo.

scholarly journals Novel Antimicrobial Peptides from the Arctic Polychaeta Nicomache minor Provide New Molecular Insight into Biological Role of the BRICHOS Domain

Marine Drugs ◽  
2018 ◽  
Vol 16 (11) ◽  
pp. 401 ◽  
Author(s):  
Pavel Panteleev ◽  
Andrey Tsarev ◽  
Ilia Bolosov ◽  
Alexander Paramonov ◽  
Mariana Marggraf ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Signal Sequence ◽  
Membrane Damage ◽  
Disulfide Bridge ◽  
The Arctic ◽  
Resonance Spectroscopy ◽  
Host Defense Peptides ◽  
Sequence Region ◽  
Α Helix

Endogenous antimicrobial peptides (AMPs) are among the earliest molecular factors in the evolution of animal innate immunity. In this study, novel AMPs named nicomicins were identified in the small marine polychaeta Nicomache minor in the Maldanidae family. Full-length mRNA sequences encoded 239-residue prepropeptides consisting of a putative signal sequence region, the BRICHOS domain within an acidic proregion, and 33-residue mature cationic peptides. Nicomicin-1 was expressed in the bacterial system, and its spatial structure was analyzed by circular dichroism and nuclear magnetic resonance spectroscopy. Nicomicins are unique among polychaeta AMPs scaffolds, combining an amphipathic N-terminal α-helix and C-terminal extended part with a six-residue loop stabilized by a disulfide bridge. This structural arrangement resembles the Rana-box motif observed in the α-helical host-defense peptides isolated from frog skin. Nicomicin-1 exhibited strong in vitro antimicrobial activity against Gram-positive bacteria at submicromolar concentrations. The main mechanism of nicomicin-1 action is based on membrane damage but not on the inhibition of bacterial translation. The peptide possessed cytotoxicity against cancer and normal adherent cells as well as toward human erythrocytes.

Inhibition of the Activities of α2-Plasmin inhibitor (PI) and CI inhibitor (CI-Inh) by the Synthetic Fibrinolytic Agent, 3-Hydroxypropyl Flufenamide (Flu-HPA)

1979 ◽  
Author(s):  
L Miles ◽  
J Burnier ◽  
M Verlander ◽  
M Goodman ◽  
A Kleiss ◽  
...  
Keyword(s):  
Plasminogen Activators ◽  
Inhibitory Effect ◽  
Mechanisms Of Action ◽  
Flufenamic Acid ◽  
Clot Lysis ◽  
Factor Xiia ◽  
Dependent Inhibition ◽  
Normal Human ◽  
Plasmin Inhibitor

Flu-HPA is one of a series of flufenamic acid derivations that enhances plasminogen-dependent clot lysis in vitro. Studies of possible mechanisms of action of Flu-HPA were undertaken. The influence of Flu-HPA on the inhibition of purified plasmin by purified PI was studied. PI activity was assessed by its inhibition of the clevage of the tripeptide S-2251 (H-D-Val-Leu-Lys-pNA) by plasmin. Flu-HPA was dissolved in DMF or in methonol and preincubated with PI before addition of plasmin. At Flu-HPA concentrations greater than 1mM and up to 60mM, the inhibitory activity of PI was totally lost. The inhibitory effect of normal human plasma on plasmin was also completely abolished at concentrations of Flu-HPA between 2.5 and 40mM. The effect of Flu-HPA on the inhibition of purified plasma kallikrein by purified CI-Inh was also studied. CI-Inh activity was measured by its inhibition of cleavage of the tripeptide Bz-Pro-Phe-Arg-pNA by kallikrein. When Flu-HPA, dissolved in DMF or in methonol, was preincubated with CI-Inh, a concentration dependent inhibition of CI-Inh activity was observed. CI-Inh activity was abolished by concentrations of Flu-HPA greater than 1mM. Flu-HPA also inhibited the activity of CI-Inh on purified Factor XIIa. These observations suggest that this flufenamic acid derivative may enhance fibrinolysis not only by inhibiting PI activity but also by decreasing the inactivation of plasminogen activators by CI-Inh.

Effect and mechanisms of action of the fixed combination STW 5 in secretion and motility of human colon in vitro.

Planta Medica ◽  
2007 ◽  
Vol 73 (09) ◽  
Author(s):  
D Krüger ◽  
S Wagner ◽  
CW Hann von Weyhern ◽  
F Zeller ◽  
O Kelber ◽  
...  
Keyword(s):  
Fixed Combination ◽  
Human Colon ◽  
Mechanisms Of Action

Antimicrobial peptides for the treatment of pulmonary tuberculosis, allies or foes?

2018 ◽  
Vol 24 (10) ◽  
pp. 1138-1147
Author(s):  
Bruno Rivas-Santiago ◽  
Flor Torres-Juarez
Keyword(s):  
Pulmonary Tuberculosis ◽  
Antimicrobial Peptides ◽  
Experimental Models ◽  
New Drugs ◽  
World Health ◽  
Public Health Issue ◽  
Health Organization ◽  
Drug Resistant Strains

Tuberculosis is an ancient disease that has become a serious public health issue in recent years, although increasing incidence has been controlled, deaths caused by Mycobacterium tuberculosis have been accentuated due to the emerging of multi-drug resistant strains and the comorbidity with diabetes mellitus and HIV. This situation is threatening the goals of World Health Organization (WHO) to eradicate tuberculosis in 2035. WHO has called for the creation of new drugs as an alternative for the treatment of pulmonary tuberculosis, among the plausible molecules that can be used are the Antimicrobial Peptides (AMPs). These peptides have demonstrated remarkable efficacy to kill mycobacteria in vitro and in vivo in experimental models, nevertheless, these peptides not only have antimicrobial activity but also have a wide variety of functions such as angiogenesis, wound healing, immunomodulation and other well-described roles into the human physiology. Therapeutic strategies for tuberculosis using AMPs must be well thought prior to their clinical use; evaluating comorbidities, family history and risk factors to other diseases, since the wide function of AMPs, they could lead to collateral undesirable effects.

Antimicrobial Peptides and their Multiple Effects at Sub-Inhibitory Concentrations

2020 ◽  
Vol 20 (14) ◽  
pp. 1264-1273 ◽  
Author(s):  
Bruno Casciaro ◽  
Floriana Cappiello ◽  
Walter Verrusio ◽  
Mauro Cacciafesta ◽  
Maria Luisa Mangoni
Keyword(s):  
Antimicrobial Peptides ◽  
Inhibitory Concentration ◽  
Multidrug Resistant ◽  
Mechanisms Of Action ◽  
New Drugs ◽  
Lead Compounds ◽  
Bacterial Pathogenicity ◽  
Growth Inhibitory ◽  
Resistant Strains ◽  
Conventional Antibiotics

The frequent occurrence of multidrug-resistant strains to conventional antimicrobials has led to a clear decline in antibiotic therapies. Therefore, new molecules with different mechanisms of action are extremely necessary. Due to their unique properties, antimicrobial peptides (AMPs) represent a valid alternative to conventional antibiotics and many of them have been characterized for their activity and cytotoxicity. However, the effects that these peptides cause at concentrations below the minimum growth inhibitory concentration (MIC) have yet to be fully analyzed along with the underlying molecular mechanism. In this mini-review, the ability of AMPs to synergize with different antibiotic classes or different natural compounds is examined. Furthermore, data on microbial resistance induction are reported to highlight the importance of antibiotic resistance in the fight against infections. Finally, the effects that sub-MIC levels of AMPs can have on the bacterial pathogenicity are summarized while showing how signaling pathways can be valid therapeutic targets for the treatment of infectious diseases. All these aspects support the high potential of AMPs as lead compounds for the development of new drugs with antibacterial and immunomodulatory activities.

scholarly journals Antiviral surfaces and coatings and their mechanisms of action

2021 ◽  
Vol 2 (1) ◽  
Author(s):  
Paulina D. Rakowska ◽  
Mariavitalia Tiddia ◽  
Nilofar Faruqui ◽  
Claire Bankier ◽  
Yiwen Pei ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Personal Protective Equipment ◽  
Viral Infections ◽  
Chemical Properties ◽  
Mechanisms Of Action ◽  
Consumer Products ◽  
Protective Equipment ◽  
Public Places ◽  
Virus Attachment ◽  
Physico Chemical

AbstractViral infections are a serious health challenge, and the COVID-19 pandemic has increased the demand for antiviral measures and treatments for clean surfaces, especially in public places. Here, we review a range of natural and synthetic surface materials and coatings with antiviral properties, including metals, polymers and biopolymers, graphene and antimicrobial peptides, and their underpinning antiviral mechanisms. We also discuss the physico-chemical properties of surfaces which influence virus attachment and persistence on surfaces. Finally, an overview is given of the current practices and applications of antiviral and virucidal materials and coatings in consumer products, personal protective equipment, healthcare and public settings.

scholarly journals EGCG binds intrinsically disordered N-terminal domain of p53 and disrupts p53-MDM2 interaction

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jing Zhao ◽  
Alan Blayney ◽  
Xiaorong Liu ◽  
Lauren Gandy ◽  
Weihua Jin ◽  
...  
Keyword(s):  
Large Scale ◽  
Molecular Mechanisms ◽  
Epigallocatechin Gallate ◽  
Cancer Drug ◽  
Dynamic Interactions ◽  
Cancer Drug Discovery ◽  
Intrinsically Disordered ◽  
Terminal Domain ◽  
Cancerous Cells

AbstractEpigallocatechin gallate (EGCG) from green tea can induce apoptosis in cancerous cells, but the underlying molecular mechanisms remain poorly understood. Using SPR and NMR, here we report a direct, μM interaction between EGCG and the tumor suppressor p53 (KD = 1.6 ± 1.4 μM), with the disordered N-terminal domain (NTD) identified as the major binding site (KD = 4 ± 2 μM). Large scale atomistic simulations (>100 μs), SAXS and AUC demonstrate that EGCG-NTD interaction is dynamic and EGCG causes the emergence of a subpopulation of compact bound conformations. The EGCG-p53 interaction disrupts p53 interaction with its regulatory E3 ligase MDM2 and inhibits ubiquitination of p53 by MDM2 in an in vitro ubiquitination assay, likely stabilizing p53 for anti-tumor activity. Our work provides insights into the mechanisms for EGCG’s anticancer activity and identifies p53 NTD as a target for cancer drug discovery through dynamic interactions with small molecules.

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