Gram-positive Pathogens (gram-positive + pathogen)

Distribution by Scientific Domains


Selected Abstracts


Evasion of macrophage scavenger receptor A-mediated recognition by pathogenic streptococci

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2008
Thomas Areschoug
Abstract PRR recognize conserved structures on pathogenic microbes and are important for the defense against invading microorganisms. However, accumulating evidence indicates that many pathogens have evolved mechanisms to avoid recognition by PRR. One type of PRR is the macrophage scavenger receptor A (SR-A), which has been shown to play an important role in recognition and non-opsonic phagocytosis of pathogenic bacteria. The bacterial ligands for SR-A have been suggested to be LPS or lipoteichoic acid. Here, we use murine bone marrow-derived macrophages to analyze the role of SR-A in non-opsonic phagocytosis of two major Gram-positive pathogens, Streptococcus agalactiae (group B streptococcus; GBS) and Streptococcus pyogenes. We show that the polysaccharide capsule of GBS and the surface M protein of S. pyogenes, two important virulence factors, prevent SR-A-mediated non-opsonic phagocytosis of streptococci. The sialic acid moiety of the GBS capsule was crucial for its ability to prevent recognition by SR-A. Moreover, we show that a ligand on GBS recognized by SR-A in the absence of capsule is the surface lipoprotein Blr. These findings represent the first example of a microbial strategy to prevent recognition by SR-A and suggest that bacterial surface proteins may be of importance as ligands for SR-A. [source]


The generation of nisin variants with enhanced activity against specific Gram-positive pathogens

MOLECULAR MICROBIOLOGY, Issue 1 2008
Des Field
Summary Nisin is the prototype of the lantibiotic group of antimicrobial peptides. It exhibits broad spectrum inhibition of Gram-positive bacteria including important food pathogens and clinically relevant antibiotic-resistant bacteria. Significantly, the gene-encoded nature of nisin means that it can be subjected to gene-based bioengineering to generate novel derivatives. Here, we take advantage of this to generate the largest bank of randomly mutated nisin derivatives reported to date, with the ultimate aim of identifying variants with enhanced bioactivity. This approach led to the identification of a nisin-producing strain with enhanced bioactivity against the mastitic pathogen Streptococcus agalactiae resulting from an amino acid change in the hinge region of the peptide (K22T). Prompted by this discovery, site-directed and site-saturation mutagenesis of the hinge region residues was employed, resulting in the identification of additional derivatives, most notably N20P, M21V and K22S, with enhanced bioactivity and specific activity against Gram-positive pathogens including Listeria monocytogenes and/or Staphylococcus aureus. The identification of these derivatives represents a major step forward in the bioengineering of nisin, and lantibiotics in general, and confirms that peptide engineering can deliver derivatives with enhanced antimicrobial activity against specific problematic spoilage and pathogenic microbes or against Gram-positive bacteria in general. [source]


The Mga virulence regulon: infection where the grass is greener

MOLECULAR MICROBIOLOGY, Issue 5 2007
Elise R. Hondorp
Summary Co-ordinate regulation of virulence gene expression in response to different host environments is central to the success of the group A streptococcus (GAS, Streptococcus pyogenes) as an important human pathogen. Mga represents a ubiquitous stand-alone virulence regulator that controls genes (Mga regulon) whose products are necessary for adherence, internalization and host immune evasion. Mga highly activates a core set of virulence genes, including its own gene, by directly binding to their promoters. Yet, Mga also influences expression of over 10% of the GAS genome, primarily genes and operons involved in metabolism and sugar utilization. Expression of the Mga regulon is influenced by conditions that signify favourable growth conditions, presumably allowing GAS to take advantage of promising new niches in the host. The ability of Mga to respond to growth signals clearly involves regulation of mga expression via global regulatory networks such as RALPs, Rgg/RopB and the catabolite control protein CcpA. However, the presence of predicted PTS regulatory domains (PRDs) within Mga suggests an intriguing model whereby phosphorylation of Mga by the PTS phosphorelay might link growth and sugar utilization with virulence in GAS. As Mga homologues have been found in several important Gram-positive pathogens, the Mga regulon could provide a valuable paradigm for increasing our understanding of global virulence networks in bacteria. [source]


Genome-wide analysis of the general stress response in Bacillus subtilis

MOLECULAR MICROBIOLOGY, Issue 4 2001
Chester W. Price
Bacteria respond to diverse growth-limiting stresses by producing a large set of general stress proteins. In Bacillus subtilis and related Gram-positive pathogens, this response is governed by the ,B transcription factor. To establish the range of cellular functions associated with the general stress response, we compared the transcriptional profiles of wild and mutant strains under conditions that induce ,B activity. Macroarrays representing more than 3900 annotated reading frames of the B. subtilis genome were hybridized to 33P-labelled cDNA populations derived from (i) wild-type and sigB mutant strains that had been subjected to ethanol stress; and (ii) a strain in which ,B expression was controlled by an inducible promoter. On the basis of their significant ,B -dependent expression in three independent experiments, we identified 127 genes as prime candidates for members of the ,B regulon. Of these genes, 30 were known previously or inferred to be ,B dependent by other means. To assist in the analysis of the 97 new genes, we constructed hidden Markov models (HMM) that identified possible ,B recognition sequences preceding 21 of them. To test the HMM and to provide an independent validation of the hybridization experiments, we mapped the ,B -dependent messages for seven representative genes. For all seven, the 5, end of the message lay near typical ,B recognition sequences, and these had been predicted correctly by the HMM for five of the seven examples. Lastly, all 127 gene products were assigned to functional groups by considering their similarity to known proteins. Notably, products with a direct protective function were in the minority. Instead, the general stress response increased relative message levels for known or predicted regulatory proteins, for transporters controlling solute influx and efflux, including potential drug efflux pumps, and for products implicated in carbon metabolism, envelope function and macromolecular turnover. [source]


Inhibitory properties and X-ray crystallographic study of the binding of AR-101, AR-102 and iclaprim in ternary complexes with NADPH and dihydrofolate reductase from Staphylococcus aureus

ACTA CRYSTALLOGRAPHICA SECTION D, Issue 8 2009
Christian Oefner
Iclaprim is a novel dihydrofolate reductase (DHFR) inhibitor belonging to the 2,4-diaminopyrimidine class of antibiotics, of which trimethoprim (TMP) is the most well known representative. Iclaprim exhibits potent bactericidal activity against major Gram-positive pathogens, notably methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) phenotypes, including TMP-resistant strains. The inhibition properties of racemic iclaprim and of the two enantiomers, termed AR-101 and AR-102, towards S. aureus wild-type DHFR and TMP-resistant F98Y mutant DHFR were determined and compared. Similar to TMP, AR-101, AR-102 and iclaprim are all competitive inhibitors with respect to the substrate dihydrofolate. Iclaprim, AR-101 and AR-102 demonstrated little or no difference in activity towards these enzymes and were significantly more potent than TMP. The crystal structures of S. aureus DHFR and F98Y mutant DHFR were determined as ternary complexes with NADPH and either AR-101, AR-102 or iclaprim. The binding modes of the inhibitors were analysed and compared. The X-ray crystallographic data explain the binding modes of all molecules well and can be used to rationalize the equipotent affinity of AR-101, AR-102 and iclaprim, which is also reflected in their antibacterial properties. [source]


From genomics via proteomics to cellular physiology of the Gram-positive model organism Bacillus subtilis

CELLULAR MICROBIOLOGY, Issue 8 2005
Uwe Völker
Summary Complementing proteomic technologies enable an unbiased view of cellular adaptation and thus may provide a new understanding of cellular physiology, particularly for microorganisms because a major fraction of their proteome is accessible to currently available technology. In combination with transcriptional profiling expression proteomics provides access to interesting candidate genes and proteins that will then need to be validated and supplemented by traditional physiological, biochemical and genetic approaches. After a description of the current status of the technology, we display the potential of microbial proteomics using the model organism Bacillus subtilis as example. Starting from a proteome map a proteomic view of the metabolism will be provided. Furthermore, we demonstrate that proteomics complemented by transcriptomics is also useful for the study of stress and starvation responses and that integration of these data will lead to a comprehensive understanding of the adaptational network of bacterial cells. Thus, B. subtilis constitutes a highly versatile and tractable model organism for the study of generic stress responses and the expertise that has been gained can easily be transferred to the study of the cellular physiology of related Gram-positive pathogens and their pathophysiology. [source]


Medicinal Chemistry Optimization of Acyldepsipeptides of the Enopeptin Class Antibiotics

CHEMMEDCHEM, Issue 7 2006
Berthold Hinzen
The therapy of life-threatening infections is significantly weakened by the global spread of antibiotic resistance. Synthetic exploration of enopeptin type acyldepsipeptide antibiotics revealed a remarkable structure,activity relationship. New compounds with improved in,vitro antibiotic activity against Gram-positive pathogens (including multiresistant strains) and in,vivo activity in mouse models of lethal infection are described. [source]


Fighting infections due to multidrug-resistant Gram-positive pathogens

CLINICAL MICROBIOLOGY AND INFECTION, Issue 3 2009
G. Cornaglia Guest Editor
Growing bacterial resistance in Gram-positive pathogens means that what were once effective and inexpensive treatments for infections caused by these bacteria are now being seriously questioned, including penicillin and macrolides for use against pneumococcal infections and,in hospitals,oxacillin for use against staphylococcal infections. As a whole, multidrug-resistant (MDR) Gram-positive pathogens are rapidly becoming an urgent and sometimes unmanageable clinical problem. Nevertheless, and despite decades of research into the effects of antibiotics, the actual risk posed to human health by antibiotic resistance has been poorly defined; the lack of reliable data concerning the outcomes resulting from antimicrobial resistance stems, in part, from problems with study designs and the methods used in resistence determination. Surprisingly little is known, too, about the actual effectiveness of the many types of intervention aimed at controlling antibiotic resistance. New antibiotics active against MDR Gram-positive pathogens have been recently introduced into clinical practice, and the antibiotic pipeline contains additional compounds at an advanced stage of development, including new glycopeptides, new anti-methicillin-resistant Staphylococcus aureus (MRSA) ,-lactams, and new diaminopyrimidines. Many novel antimicrobial agents are likely to be niche products, endowed with narrow antibacterial spectra and/or targeted at specific clinical problems. Therefore, an important educational goal will be to change the current, long-lasting attitudes of both physicians and customers towards broad-spectrum and multipurpose compounds. Scientific societies, such as the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), must play a leading role in this process. [source]


Clinical impact of antibiotic-resistant Gram-positive pathogens

CLINICAL MICROBIOLOGY AND INFECTION, Issue 3 2009
H. M. Lode
Abstract The European Union's attention to the problem of antibacterial resistance will soon reach a 10-year mark, but the rates of resistance in Gram-positive and Gram-negative bacteria are still increasing. This review focuses on the clinical impact of resistant Gram-positive bacteria on patients. Multiple drug resistance in pneumococcal infections will lead to more treatment failures and higher mortality, which so far have been seen with penicillins and pathogens with high-level resistance. Several studies have demonstrated higher mortality, prolonged length of hospital stay and higher costs associated with methicillin-resistant Staphylococcus aureus infections, in comparison with methicillin-susceptible Staphylococcus aureus infections. Similarly, vancomycin-resistant enterococci bloodstream infections have a negative impact with respect to mortality, length of hospital stay and costs, in comparison with infections due to vancomycin-susceptible enterococci. Several distinctive prophylactic and therapeutic approaches have to be undertaken to successfully prevent the clinical consequences of antibiotic resistance in Gram-positive bacteria. This review addresses the impact of antibiotic-resistant Gram-positive pathogens on clinical outcomes. [source]


Key considerations in the treatment of complicated staphylococcal infections

CLINICAL MICROBIOLOGY AND INFECTION, Issue 2008
R. N. Jones
Abstract Substantial increases in antimicrobial resistance among Gram-positive pathogens, particularly Staphylococcus aureus, are compromising traditional therapies for serious bacterial infections. There has been an alarming increase in the rates of methicillin-resistant S. aureus (MRSA) over the past two decades, and the more recent emergence of heterogenous vancomycin-intermediate (hVISA), vancomycin-intermediate (VISA) and vancomycin-resistant S. aureus (VRSA) strains limits the use of vancomycin, the current standard of care for MRSA infections. Tolerance to vancomycin, which represents a lack of bactericidal activity of vancomycin, is another troublesome property of some S. aureus strains that can adversely affect the outcome of antimicrobial therapy. Increasing MICs of vancomycin for staphylococci, poor tissue penetration by the drug and a slow rate of bactericidal action of the drug have also raised concerns about its efficacy in the contemporary treatment of MRSA infections. There is an increasingly apparent need for new agents for the treatment of staphylococcal infections, ideally with potent bactericidal activity against MRSA, hVISA, VISA and VRSA and with superior susceptibility profiles as compared with glycopeptides. [source]


Crystal structure of the Streptococcus pneumoniae mevalonate kinase in complex with diphosphomevalonate

PROTEIN SCIENCE, Issue 5 2007
John L. Andreassi II
Abstract Streptococcuspneumoniae, a ubiquitous gram-positive pathogen with an alarming, steadily evolving resistance to frontline antimicrobials, poses a severe global health threat both in the community and in the clinic. The recent discovery that diphosphomevalonate (DPM), an essential intermediate in the isoprenoid biosynthetic pathway, potently and allosterically inhibits S. pneumoniae mevalonate kinase (SpMK) without affecting the human isozyme established a new target and lead compound for antimicrobial design. Here we present the crystal structure of the first S. pneumoniae mevalonate kinase, at a resolution of 2.5 Å and in complex with DPM·Mg2+ in the active-site cleft. Structural comparison of SpMK with other members of the GHMP kinase family reveals that DPM functions as a partial bisubstrate analog (mevalonate linked to the pyrophosphoryl moiety of ATP) in that it elicits a ternary-complexlike form of the enzyme, except for localized disordering in a region that would otherwise interact with the missing portion of the nucleotide. Features of the SpMK-binding pockets are discussed in the context of established mechanistic findings and inherited human diseases linked to MK deficiency. [source]