scholarly journals Defense against own arms: staphylococcal cysteine proteases and their inhibitors.

2003 ◽  
Vol 50 (3) ◽  
pp. 715-724 ◽  
Author(s):  
Grzegorz Dubin
Keyword(s):  
Staphylococcus Aureus ◽  
Protease Inhibitors ◽  
Current Knowledge ◽  
Cysteine Proteases ◽  
Infection Process ◽  
Secreted Proteins ◽  
Human Pathogen ◽  
Cysteine Protease Inhibitors ◽  
Wide Range

Staphylococcus aureus is a human pathogen causing a wide range of diseases. Most staphylococcal infections, unlike those caused by other bacteria are not toxigenic and very little is known about their pathogenesis. It has been proposed that a core of secreted proteins common to many infectious strains is responsible for colonization and infection. Among those proteins several proteases are present and over the years many different functions in the infection process have been attributed to them. However, little direct, in vivo data has been presented. Two cysteine proteases, staphopain A (ScpA) and staphopain B (SspB) are important members of this group of enzymes. Recently, two cysteine protease inhibitors, staphostatin A and staphostatin B (ScpB and SspC, respectively) were described in S. aureus shedding new light on the complexity of the processes involving the two proteases. The scope of this review is to summarize current knowledge on the network of staphylococcal cysteine proteases and their inhibitors in view of their possible role as virulence factors.

scholarly journals Inhibition of Staphylococcus aureus cysteine proteases by human serpin potentially limits staphylococcal virulence

2011 ◽  
Vol 392 (5) ◽  
Author(s):  
Tomasz Kantyka ◽  
Karolina Plaza ◽  
Joanna Koziel ◽  
Danuta Florczyk ◽  
Hennig R. Stennicke ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Serine Proteases ◽  
Peptide Bond ◽  
Cysteine Proteases ◽  
Reactive Site ◽  
Association Rate ◽  
High Association ◽  
Endogenous Protease ◽  
Covalent Complex

AbstractBacterial proteases are considered virulence factors and it is presumed that by abrogating their activity, host endogenous protease inhibitors play a role in host defense against invading pathogens. Here we present data showing thatStaphylococcus aureuscysteine proteases (staphopains) are efficiently inhibited by Squamous Cell Carcinoma Antigen 1 (SCCA1), an epithelial-derived serpin. The high association rate constant (kass) for inhibitory complex formation (1.9×104m/s and 5.8×104 m/s for staphopain A and staphopain B interaction with SCCA1, respectively), strongly suggests that SCCA1 can regulate staphopain activityin vivoat epithelial surfaces infected/colonized byS. aureus. The mechanism of staphopain inhibition by SCCA1 is apparently the same for serpin interaction with target serine proteases whereby the formation of a covalent complex result in cleavage of the inhibitory reactive site peptide bond and associated release of the C-terminal serpin fragment. Interestingly, the SCCA1 reactive site closely resembles a motif in the reactive site loop of nativeS. aureus-derived inhibitors of the staphopains (staphostatins). Given thatS. aureusis a major pathogen of epithelial surfaces, we suggest that SCCA1 functions to temper the virulence of this bacterium by inhibiting the staphopains.

scholarly journals Structure-Function of Falcipains: Malarial Cysteine Proteases

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Kailash C. Pandey ◽  
Rajnikant Dixit
Keyword(s):  
Functional Analysis ◽  
Drug Development ◽  
Protease Inhibitors ◽  
Cysteine Protease ◽  
Essential Role ◽  
Cysteine Proteases ◽  
Structural Studies ◽  
Cysteine Protease Inhibitors ◽  
Hemoglobin Binding ◽  
Structural Insight

Evidence indicates that cysteine proteases play essential role in malaria parasites; therefore an obvious area of investigation is the inhibition of these enzymes to treat malaria. Studies with cysteine protease inhibitors and manipulating cysteine proteases genes have suggested a role for cysteine proteases in hemoglobin hydrolysis. The best characterizedPlasmodiumcysteine proteases are falcipains, which are papain family enzymes. Falcipain-2 and falcipain-3 are major hemoglobinases ofP. falciparum. Structural and functional analysis of falcipains showed that they have unique domains including a refolding domain and a hemoglobin binding domain. Overall, the complexes of falcipain-2 and falcipain-3 with small and macromolecular inhibitors provide structural insight to facilitate the design or modification of effective drug treatment against malaria. Drug development targeting falcipains should be aided by a strong foundation of biochemical and structural studies.

scholarly journals The Diverse Roles of the Global Transcriptional Regulator PhoP in the Lifecycle of Yersinia pestis

Pathogens ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1039
Author(s):  
Hana S. Fukuto ◽  
Gloria I. Viboud ◽  
Viveka Vadyvaloo
Keyword(s):  
Yersinia Pestis ◽  
Current Knowledge ◽  
Response Regulator ◽  
Expression Profiles ◽  
Critical Role ◽  
Gene Expression Profiles ◽  
Acanthamoeba Castellanii ◽  
Wide Range

Yersinia pestis, the causative agent of plague, has a complex infectious cycle that alternates between mammalian hosts (rodents and humans) and insect vectors (fleas). Consequently, it must adapt to a wide range of host environments to achieve successful propagation. Y. pestis PhoP is a response regulator of the PhoP/PhoQ two-component signal transduction system that plays a critical role in the pathogen’s adaptation to hostile conditions. PhoP is activated in response to various host-associated stress signals detected by the sensor kinase PhoQ and mediates changes in global gene expression profiles that lead to cellular responses. Y. pestis PhoP is required for resistance to antimicrobial peptides, as well as growth under low Mg2+ and other stress conditions, and controls a number of metabolic pathways, including an alternate carbon catabolism. Loss of phoP function in Y. pestis causes severe defects in survival inside mammalian macrophages and neutrophils in vitro, and a mild attenuation in murine plague models in vivo, suggesting its role in pathogenesis. A Y. pestisphoP mutant also exhibits reduced ability to form biofilm and to block fleas in vivo, indicating that the gene is also important for establishing a transmissible infection in this vector. Additionally, phoP promotes the survival of Y. pestis inside the soil-dwelling amoeba Acanthamoeba castellanii, a potential reservoir while the pathogen is quiescent. In this review, we summarize our current knowledge on the mechanisms of PhoP-mediated gene regulation in Y. pestis and examine the significance of the roles played by the PhoP regulon at each stage of the Y. pestis life cycle.

scholarly journals Structure-Activity Relationships for Inhibition of Cysteine Protease Activity and Development of Plasmodium falciparum by Peptidyl Vinyl Sulfones

2003 ◽  
Vol 47 (1) ◽  
pp. 154-160 ◽  
Author(s):  
Bhaskar R. Shenai ◽  
Belinda J. Lee ◽  
Alejandro Alvarez-Hernandez ◽  
Pek Y. Chong ◽  
Cory D. Emal ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Cysteine Protease ◽  
Cysteine Proteases ◽  
Parasite Development ◽  
Vinyl Sulfone ◽  
Cysteine Protease Inhibitors ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Sulfonate Ester

ABSTRACT The Plasmodium falciparum cysteine proteases falcipain-2 and falcipain-3 appear to be required for hemoglobin hydrolysis by intraerythrocytic malaria parasites. Previous studies showed that peptidyl vinyl sulfone inhibitors of falcipain-2 blocked the development of P. falciparum in culture and exerted antimalarial effects in vivo. We now report the structure-activity relationships for inhibition of falcipain-2, falcipain-3, and parasite development by 39 new vinyl sulfone, vinyl sulfonate ester, and vinyl sulfonamide cysteine protease inhibitors. Levels of inhibition of falcipain-2 and falcipain-3 were generally similar, and many potent compounds were identified. Optimal antimalarial compounds, which inhibited P. falciparum development at low nanomolar concentrations, were phenyl vinyl sulfones, vinyl sulfonate esters, and vinyl sulfonamides with P2 leucine moieties. Our results identify independent structural correlates of falcipain inhibition and antiparasitic activity and suggest that peptidyl vinyl sulfones have promise as antimalarial agents.

scholarly journals Natural Variability of In Vitro Adherence to Fibrinogen and Fibronectin Does Not Correlate with In Vivo Infectivity of Staphylococcus aureus

2010 ◽  
Vol 78 (4) ◽  
pp. 1711-1716 ◽  
Author(s):  
Mathilde Ythier ◽  
Jose M. Entenza ◽  
Jacques Bille ◽  
François Vandenesch ◽  
Michèle Bes ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Rat Model ◽  
Apparent Paradox ◽  
Gene Redundancy ◽  
Wide Range ◽  
Differential Gene ◽  
Human Host Factors ◽  
The Relationship

ABSTRACT Adherence to fibrinogen and fibronectin plays a crucial role in Staphylococcus aureus experimental endocarditis. Previous genetic studies have shown that infection and carriage isolates do not systematically differ in their virulence-related genes, including genes conferring adherence, such as clfA and fnbA. We set out to determine the range of adherence phenotypes in carriage isolates of S. aureus, to compare the adherence of these isolates to the adherence of infection isolates, and to determine the relationship between adherence and infectivity in a rat model of experimental endocarditis. A total of 133 healthy carriage isolates were screened for in vitro adherence to fibrinogen and fibronectin, and 30 isolates were randomly chosen for further investigation. These 30 isolates were compared to 30 infective endocarditis isolates and 30 blood culture isolates. The infectivities of the carriage isolates, which displayed either extremely low or high adherence to fibrinogen and fibronectin, were tested using a rat model of experimental endocarditis. The levels of adherence to both fibrinogen and fibronectin were very similar for isolates from healthy carriers and members of the two groups of infection isolates. All three groups of isolates showed a wide range of adherence to fibrinogen and fibronectin. Moreover, the carriage isolates that showed minimal adherence and the carriage isolates that showed strong adherence had the same infectivity in experimental endocarditis. Adherence was proven to be important for pathogenesis in experimental endocarditis, but even the least adherent carriage strains had the ability to induce infection. We discuss the roles of differential gene expression, human host factors, and gene redundancy in resolving this apparent paradox.

scholarly journals Phage Therapy as a Focused Management Strategy in Aquaculture

2021 ◽  
Vol 22 (19) ◽  
pp. 10436
Author(s):  
José Ramos-Vivas ◽  
Joshua Superio ◽  
Jorge Galindo-Villegas ◽  
Félix Acosta
Keyword(s):  
Bacterial Infections ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Control Strategies ◽  
Bacterial Species ◽  
Lytic Enzymes ◽  
Wide Range ◽  
Cultured Fish

Therapeutic bacteriophages, commonly called as phages, are a promising potential alternative to antibiotics in the management of bacterial infections of a wide range of organisms including cultured fish. Their natural immunogenicity often induces the modulation of a variated collection of immune responses within several types of immunocytes while promoting specific mechanisms of bacterial clearance. However, to achieve standardized treatments at the practical level and avoid possible side effects in cultivated fish, several improvements in the understanding of their biology and the associated genomes are required. Interestingly, a particular feature with therapeutic potential among all phages is the production of lytic enzymes. The use of such enzymes against human and livestock pathogens has already provided in vitro and in vivo promissory results. So far, the best-understood phages utilized to fight against either Gram-negative or Gram-positive bacterial species in fish culture are mainly restricted to the Myoviridae and Podoviridae, and the Siphoviridae, respectively. However, the current functional use of phages against bacterial pathogens of cultured fish is still in its infancy. Based on the available data, in this review, we summarize the current knowledge about phage, identify gaps, and provide insights into the possible bacterial control strategies they might represent for managing aquaculture-related bacterial diseases.

scholarly journals Immune System Evasion Mechanisms in Staphylococcus aureus: Current Understanding

2020 ◽  
Vol 14 (4) ◽  
pp. 2219-2234
Author(s):  
Hesham A. Malak ◽  
Hussein H. Abulreesh ◽  
Sameer R. Organji ◽  
Khaled Elbanna ◽  
Mohammed R. Shaaban ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Immune System ◽  
Soft Tissue ◽  
Immune Cells ◽  
Bloodstream Infections ◽  
Host Cells ◽  
Human Pathogen ◽  
Immune Systems ◽  
Wide Range ◽  
New Strategy

Staphylococcus aureus is a major human pathogen that may cause a wide range of infections and is a frequent cause of soft tissue and bloodstream infections. It is a successful pathogen due to its collective virulence factors and its ability to evade the host immune systems. The review aims to highlight how S. aureus destroys and damage the host cells and explains how immune cells can respond to this pathogen. This review may also provide new insights that may be useful for developing new strategy for combating MRSA and its emerging clones such as community-associated methicillin-resistant S. aureus (CA-MRSA).

When antibiotics fail: a clinical and microbiological perspective on antibiotic tolerance and persistence of Staphylococcus aureus

2020 ◽  
Vol 75 (5) ◽  
pp. 1071-1086 ◽  
Author(s):  
Richard Kuehl ◽  
Laura Morata ◽  
Sylvain Meylan ◽  
Josep Mensa ◽  
Alex Soriano
Keyword(s):  
Staphylococcus Aureus ◽  
Molecular Mechanisms ◽  
Clinical Evidence ◽  
Current Knowledge ◽  
Physiological Changes ◽  
Human Pathogen ◽  
Clinical Context ◽  
Frequent Failure ◽  
Microbiological Assays ◽  
Significant Mortality

Abstract Staphylococcus aureus is a major human pathogen causing a vast array of infections with significant mortality. Its versatile physiology enables it to adapt to various environments. Specific physiological changes are thought to underlie the frequent failure of antimicrobial therapy despite susceptibility in standard microbiological assays. Bacteria capable of surviving high antibiotic concentrations despite having a genetically susceptible background are described as ‘antibiotic tolerant’. In this review, we put current knowledge on environmental triggers and molecular mechanisms of increased antibiotic survival of S. aureus into its clinical context. We discuss animal and clinical evidence of its significance and outline strategies to overcome infections with antibiotic-tolerant S. aureus.

Synthesis of quinoline derivatives as potential cysteine protease inhibitors

2020 ◽  
Author(s):  
Marina MS Andrade ◽  
Luan C Martins ◽  
Gabriel VL Marques ◽  
Carla A Silva ◽  
Gilson Faria ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Protease Inhibitors ◽  
Cysteine Protease ◽  
Inhibitory Activity ◽  
Molecular Targets ◽  
Cysteine Proteases ◽  
Leishmania Species ◽  
Molecular Target ◽  
Quinoline Derivatives ◽  
Cysteine Protease Inhibitors

Aim: Cysteine proteases are important molecular targets involved in the replication, virulence and survival of parasitic organisms, including Trypanosoma and Leishmania species. Methodology & results: Analogs of the 7-chloro- N-[3-(morpholin-4-yl)propyl]quinolin-4-amine were synthesized and their inhibitory activity against the enzymes cruzain and rhodesain as well as against promastigotes forms of Leishmania species and epimastigotes forms of Trypanosoma cruzi were evaluated. Five compounds showed activity against both enzymes with IC50 values ranging from 23 to 123 μM. Among these, compounds 3 and 4 displayed leishmanicidal activity; compound 4 was the most promising with IC50 values <10 μM and no cytotoxicity for uninfected cells. Conclusion: The results obtained indicate that cysteine proteases are likely to be the molecular target of compounds 3 and 4.

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