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
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.
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.
The use of β-lactam antibiotics to treat infections caused by Staphylococcus aureus has been severely compromised by the acquisition by horizontal gene transfer of a gene that encodes the ...β-lactam-insensitive penicillin-binding protein PBP2a. This allows methicillin-resistant S. aureus (MRSA) to proliferate in the presence of β-lactam antibiotics. Paradoxically the dependence on PBP2a for the essential transpeptidase activity in cell wall peptidoglycan biosynthesis is the ‘Achilles heel’ of MRSA. Compounds that disrupt the divisome, wall teichoic acid, and functional membrane microdomains act synergistically with β-lactams against MRSA. These include drugs such as statins that are widely used in human medicine. The antibiotics vancomycin and daptomycin are also synergistic with β-lactams, and combinations have been employed to treat persistent MRSA infections. An additional benefit of exposing MRSA to β-lactams could be a reduction in virulence mediated by interfering with the global regulator Agr. The mechanistic basis of synergy is discussed, and the possibility that β-lactams can be resurrected to combat MRSA infections is explored.
While the penicillin-binding protein PBP2a allows MRSA to synthesize peptidoglycan in the presence of β-lactam antibiotics, PBP2a is also its ‘Achilles heel’.
Compounds that interfere with the stability of PBP2a by inhibiting functional membrane microdomains, wall teichoic acid, or the PrsA chaperone render MRSA susceptible to β-lactam antibiotics.
Compounds that interfere with protein secretion or the divisome act synergistically with β-lactam antibiotics.
Daptomycin acts synergistically with β-lactams that target PBP1 and have been used together to treat persistent MRSA infections.
Daptomycin-resistant MRSA strains are sensitized to β-lactams that target PBP2 because of failure to link to the membrane the PrsA chaperone lipoprotein needed for PBP2a stability.
β-Lactams can reduce the virulence of MRSA by making it more susceptible to host antimicrobial peptides and by reducing toxin expression.
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.
is a species of coagulase-negative staphylococcus (CoNS) that causes serious infections in humans akin to those of
It was often misidentified as
, but this has been rectified by recent routine use of ...matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) in diagnostic laboratories. It encodes a diverse array of virulence factors for adhesion, cytotoxicity, and innate immune evasion, but these are less diverse than those encoded by
It expresses an iron-regulated surface determinant (Isd) system combined with a novel energy-coupling factor (ECF) mechanism for extracting heme from hemoproteins. Small cytolytic
synergistic hemolysins (SLUSH), peptides related to phenol-soluble modulins of
, act synergistically with β-toxin to lyse erythrocytes.
expresses a novel peptide antibiotic, lugdunin, that can influence the nasal and skin microbiota. Endovascular infections are initiated by bacterial adherence to fibrinogen promoted by a homologue of
clumping factor A and to von Willebrand factor on damaged endothelium by an uncharacterized mechanism.
survives within mature phagolysosomes of macrophages without growing and is released only following apoptosis. This differs fundamentally from
, which actively grows and expresses bicomponent leukotoxins that cause membrane damage and could contribute to survival in the infected host.
is being investigated as a probiotic to eradicate
from the nares of carriers. However, this is contraindicated by its innate virulence. Studies to obtain a deeper understanding of
colonization, virulence, and microbiome interactions are therefore warranted.
Staphylococcus aureus is an important opportunistic pathogen and persistently colonizes about 20% of the human population. Its surface is 'decorated' with proteins that are covalently anchored to the ...cell wall peptidoglycan. Structural and functional analysis has identified four distinct classes of surface proteins, of which microbial surface component recognizing adhesive matrix molecules (MSCRAMMs) are the largest class. These surface proteins have numerous functions, including adhesion to and invasion of host cells and tissues, evasion of immune responses and biofilm formation. Thus, cell wall-anchored proteins are essential virulence factors for the survival of S. aureus in the commensal state and during invasive infections, and targeting them with vaccines could combat S. aureus infections.
Staphylococcus aureus can cause superficial skin infections and, occasionally, deep-seated infections that entail spread through the blood stream. The organism expresses several factors that ...compromise the effectiveness of neutrophils and macrophages, the first line of defence against infection. S. aureus secretes proteins that inhibit complement activation and neutrophil chemotaxis or that lyse neutrophils, neutralizes antimicrobial defensin peptides, and its cell surface is modified to reduce their effectiveness. The organism can survive in phagosomes, express polysaccharides and proteins that inhibit opsonization by antibody and complement, and its cell wall is resistant to lysozyme. Furthermore, S. aureus expresses several types of superantigen that corrupt the normal humoral immune response, resulting in anergy and immunosuppression. In contrast, Staphylococcus epidermidis must rely primarily on cell-surface polymers and the ability to form a biolfilm to survive in the host.
Male lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) is common in men and can have negative effects on quality of life (QoL). It is the hope that this Guideline ...becomes a reference on the effective evidence-based surgical management of LUTS/BPH.
The evidence team searched Ovid MEDLINE, the Cochrane Library, and the Agency for Healthcare Research and Quality (AHRQ) database to identify studies indexed between January 2007 and September 2017. When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions (table 1 in supplementary unabridged guideline, http://jurology.com/).
This Guideline provides updated, evidence-based recommendations regarding management of LUTS/BPH utilizing surgery and minimally invasive surgical therapies; additional statements are made regarding diagnostic and pre-operative tests. Clinical statements are made in comparison to what is generally accepted as the gold standard (i.e. transurethral resection of the prostate TURP–monopolar and/or bipolar). This guideline is designed to be used in conjunction with the associated treatment algorithm.
The prevalence and the severity of LUTS increases as men age and is an important diagnosis in the healthcare of patients and the welfare of society. This document will undergo additional literature reviews and updating as the knowledge regarding current treatments and future surgical options continues to expand.
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