Abstract
The major targets for antibiotics in staphylococci are (i) the cell envelope, (ii) the ribosome and (iii) nucleic acids. Several novel targets emerged from recent targeted drug discovery ...programmes including the ClpP protease and FtsZ from the cell division machinery. Resistance can either develop by horizontal transfer of resistance determinants encoded by mobile genetic elements viz plasmids, transposons and the staphylococcal cassette chromosome or by mutations in chromosomal genes. Horizontally acquired resistance can occur by one of the following mechanisms: (i) enzymatic drug modification and inactivation, (ii) enzymatic modification of the drug binding site, (iii) drug efflux, (iv) bypass mechanisms involving acquisition of a novel drug-resistant target, (v) displacement of the drug to protect the target. Acquisition of resistance by mutation can result from (i) alteration of the drug target that prevents the inhibitor from binding, (ii) derepression of chromosomally encoded multidrug resistance efflux pumps and (iii) multiple stepwise mutations that alter the structure and composition of the cell wall and/or membrane to reduce drug access to its target. This review focuses on development of resistance to currently used antibiotics and examines future prospects for new antibiotics and informed use of drug combinations.
Staphylococcus aureus has become resistant to all antibiotics used to combat infection through acquisition of resistance mechanisms acquired by horizontal transfer and by chromosomal mutations. The current dearth of treatment options might be overcome by new discoveries and synergistic combinations
Replay Comes of Age Foster, David J
Annual review of neuroscience,
07/2017, Volume:
40, Issue:
1
Journal Article
Peer reviewed
Open access
Hippocampal place cells take part in sequenced patterns of reactivation after behavioral experience, known as replay. Since replay was first reported, nearly 20 years ago, many new results have been ...found, necessitating revision of the original interpretations. We review some of these results with a focus on the phenomenology of replay.
The microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) are a family of proteins that are defined by the presence of two adjacent IgG-like folded subdomains. These promote ...binding to ligands by mechanisms that involve major conformational changes exemplified by the binding to fibrinogen by the ‘dock-lock-latch’ mechanism or to collagen by the ‘collagen hug’. Clumping factors A and B are two such MSCRAMMs that have several important roles in the pathogenesis of Staphylococcus aureus infections. MSCRAMM architecture, ligand binding, and roles in infection and colonization are examined with a focus on recent developments with clumping factors.
Shear stress mechanical forces trigger interactions between MSCRAMMs and their ligands.MSCRAMMs bound to ligands via the dock-lock-latch or collagen-hug mechanisms can only be separated by very strong forces.Clumping factor A has a crucial role in attachment to the endothelium during endovascular infections.Clumping factor B binding to loricrin is important in early abscess formation as well as in adhesion to corneocytes.MSCRAMMs also bind a plethora of ligands by mechanisms that do not involve dock-lock-latch.
The primary structural component of the bacterial cell wall is peptidoglycan, which is essential for viability and the synthesis of which is the target for crucial antibiotics
. Peptidoglycan is a ...single macromolecule made of glycan chains crosslinked by peptide side branches that surrounds the cell, acting as a constraint to internal turgor
. In Gram-positive bacteria, peptidoglycan is tens of nanometres thick, generally portrayed as a homogeneous structure that provides mechanical strength
. Here we applied atomic force microscopy
to interrogate the morphologically distinct Staphylococcus aureus and Bacillus subtilis species, using live cells and purified peptidoglycan. The mature surface of live cells is characterized by a landscape of large (up to 60 nm in diameter), deep (up to 23 nm) pores constituting a disordered gel of peptidoglycan. The inner peptidoglycan surface, consisting of more nascent material, is much denser, with glycan strand spacing typically less than 7 nm. The inner surface architecture is location dependent; the cylinder of B. subtilis has dense circumferential orientation, while in S. aureus and division septa for both species, peptidoglycan is dense but randomly oriented. Revealing the molecular architecture of the cell envelope frames our understanding of its mechanical properties and role as the environmental interface
, providing information complementary to traditional structural biology approaches.
Staphylococcus aureus is frequently isolated from the skin of atopic dermatitis (AD) patients during flares. The normal microbiota is disrupted and the diversity of the microorganisms on the skin is ...reduced. Many species that produce inhibitors of S. aureus growth decline. Strains from S. aureus clonal complex 1 are enriched among AD sufferers whereas the CC30 strains most frequently isolated from nasal carriers in the normal population are much rarer in AD. S. aureus expresses several molecules that contribute to the intensity of symptoms, including δ-toxin which stimulates mast cells, α-toxin which damages keratinocytes, phenol-soluble modulins which stimulate cytokine release by keratinocytes, protein A which triggers inflammatory responses from keratinocytes, superantigens which trigger B cell expansion and cytokine release, and proinflammatory lipoproteins. Proteases contribute to disruption of the epidermal barrier. S. aureus isolated from AD patients adheres to the deformed corneocytes from AD patients in a clumping factor B-dependent fashion. Novel targeted therapies for AD have recently been introduced to clinical practice with many more in development, including monoclonal antibodies that specifically target cytokines and their receptors, and a bacteriophage lysin that eliminates S. aureus from AD skin.
The diversity of the skin microbiome is diminished during an AD flare, with S. aureus assuming hegemony.
Proliferation of S. aureus during AD flares is encouraged by reduced competition from the microbiota and favourable growth conditions, including higher pH.
S. aureus expresses superantigens, cytolytic α- and δ-toxins, phenol-soluble modulins, protein A, and several proteases which have roles in AD pathogenesis.
Clumping factor B promotes adhesion to deformed corneocytes in AD skin, and this is likely to be an important step in colonization.
New treatments, including a lytic enzyme that is specific for S. aureus, are in development. One specific monoclonal antibody inhibitor that targets the receptor for the type 2 cytokines IL-4 and IL-13 has recently been approved for clinical use, and many others inhibitors targeting type 2 cytokines are in development.
Flexibility is a hallmark of memories that depend on the hippocampus. For navigating animals, flexibility is necessitated by environmental changes such as blocked paths and extinguished food sources. ...To better understand the neural basis of this flexibility, we recorded hippocampal replays in a spatial memory task where barriers as well as goals were moved between sessions to see whether replays could adapt to new spatial and reward contingencies. Strikingly, replays consistently depicted new goal-directed trajectories around each new barrier configuration and largely avoided barrier violations. Barrier-respecting replays were learned rapidly and did not rely on place cell remapping. These data distinguish sharply between place field responses, which were largely stable and remained tied to sensory cues, and replays, which changed flexibly to reflect the learned contingencies in the environment and suggest sequenced activations such as replay to be an important link between the hippocampus and flexible memory.
•Rats learn to solve a goal-directed navigation task with randomly-changing barriers.•Replay adapts to the new barriers and is predictive of future behavior.•Place fields are largely stable across barrier configurations.
Widloski and Foster show that place cells in rat hippocampus learn replay sequences around barriers, even after a large (>90) number of barrier reconfigurations. By contrast, cells’ place fields are largely stable, dissociating the stable representation of space from a powerful mechanism for the acquisition and recall of flexible memory.
G-protein-coupled receptors (GPCRs) play critical roles in regulating brain function. Recent advances have greatly expanded our understanding of these receptors as complex signaling machines that can ...adopt numerous conformations and modulate multiple downstream signaling pathways. While agonists and antagonists have traditionally been pursued to target GPCRs, allosteric modulators provide several mechanistic advantages, including the ability to distinguish between closely related receptor subtypes. Recently, the discovery of allosteric ligands that confer bias and modulate some, but not all, of a given receptor’s downstream signaling pathways can provide pharmacological modulation of brain circuitry with remarkable precision. In addition, allosteric modulators with unprecedented specificity have been developed that can differentiate between subpopulations of a given receptor subtype based on the receptor’s dimerization state. These advances are not only providing insight into the biological roles of specific receptor populations, but hold great promise for treating numerous CNS disorders.
Allosteric modulators of GPCRs allow selective modulation of GPCR signaling in identified brain circuits with remarkable precision. Foster and Conn review recent advances enabled by these novel compounds as well as their potential utility in the treatment of CNS disorders.
Staphylococcus epidermidis
is a ubiquitous commensal of human skin. The widespread use of indwelling medical devices in modern medicine provides an opportunity for it to cause infections. Disease ...causing isolates can come from many different genetic backgrounds. Multiply antibiotic resistant strains have spread globally.
S. epidermidis
has a smaller repertoire of cell wall anchored (CWA) surface proteins than
Staphylococcus aureus
. Nevertheless, these CWA proteins promote adhesion to components of the extracellular matrix including collagen, fibrinogen, and fibronectin and contribute to the formation of biofilm. The A domain of the accumulation associated protein Aap can promote adhesion to unconditioned biomaterial but must be removed proteolytically to allow accumulation to proceed by homophilic Zn
2+
-dependent interactions. Mature biofilm contains amyloid structures formed by Aap and the small basic protein (Sbp). The latter contributes to the integrity of both protein and polysaccharide biofilm matrices. Several other CWA proteins can also promote
S. epidermidis
biofilm formation.
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