The Staphylococcus aureus “superbug”

Foster, Timothy J.

doi:10.1172/jci200423825

Cited by 238 publications

(134 citation statements)

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“…S. aureus produces many toxins and exoenzymes to cause various suppurative diseases, food poisoning and toxic shock syndrome (Foster, 2004;Lowy, 1998;Manders, 1998). Furthermore, strains isolated clinically, especially meticillin-resistant S. aureus (MRSA), exhibit multiple antibiotic resistance (Deurenberg et al, 2007;Grundmann et al, 2006), resulting in serious problems with regard to therapy of S. aureus infectious disease.…”

Section: Introductionmentioning

confidence: 99%

Growth-phase dependence of susceptibility to antimicrobial peptides in Staphylococcus aureus

et al. 2011

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Bacterial cell surface charge is responsible for susceptibility to cationic antimicrobial peptides. Previously, Staphylococcus aureus dlt and mprF were identified as factors conferring a positive charge upon cell surfaces. In this study, we investigated the regulation of cell surface charge during growth. Using a group of S. aureus MW2 mutants, which are gene-inactivated in 15 types of two-component systems (TCSs), we tested dltC and mprF expression and found that two TCSs, aps and agr, were associated with dltC and mprF expression in a growth phase-dependent manner. The first of these, aps, which had already been identified as a sensor of antimicrobial peptides and a positive regulator of dlt and mprF expression, was expressed strongly in the exponential phase, while its expression was significantly suppressed by agr in the stationary phase, resulting in higher expression of dltC and mprF in the exponential phase and lower expression in the stationary phase. Since both types of expression affected the cell surface charge, the susceptibility to antimicrobial peptides and cationic antibiotics was changed during growth. Furthermore, we found that the ability to sense antimicrobial peptides only functioned in the exponential phase. These results suggest that cell surface charge is tightly regulated during growth in S. aureus. INTRODUCTIONStaphylococcus aureus is a well-known major pathogen in humans. S. aureus produces many toxins and exoenzymes to cause various suppurative diseases, food poisoning and toxic shock syndrome (Foster, 2004;Lowy, 1998;Manders, 1998). Furthermore, strains isolated clinically, especially meticillin-resistant S. aureus (MRSA), exhibit multiple antibiotic resistance (Deurenberg et al., 2007;Grundmann et al., 2006), resulting in serious problems with regard to therapy of S. aureus infectious disease. Recently, besides these virulence factors, S. aureus has also been found to possess the ability to produce several factors that protect against host-derived innate immune factors, such as complement, antibodies and neutrophils, as well as recently recognized innate immune antimicrobial peptides, such as LL-37 and defensins (Foster, 2005;Rooijakkers et al., 2005).Human antimicrobial peptides are one of the innate immune factors and are produced in various tissues and organs, such as the skin, lung and intestines (Ganz et al., 1985;Ganz & Lehrer, 1995;Lehrer & Ganz, 1999;Selsted & Ouellette, 2005;Zaiou & Gallo, 2002). The most wellknown antimicrobial peptides are the defensins. Defensins are classified into two types: alpha-defensins from neutrophils and Paneth cells, and beta-defensins from epithelial cells (Cunliffe, 2003;Ganz et al., 1985;Ganz & Lehrer, 1995). Another major peptide is CAP18/LL37, which is found in neutrophils and epithelial cells (Larrick et al., 1995;Ramanathan et al., 2002;Zaiou & Gallo, 2002). These cationic peptides are electrostatically attracted to bacterial cell surfaces. Then, the peptides interact with membrane lipids, causing membrane permeabilization and leading to ...

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Section: Introductionmentioning

confidence: 99%

Growth-phase dependence of susceptibility to antimicrobial peptides in Staphylococcus aureus

et al. 2011

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“…Staphylococcus aureus is a frequent constituent of human nasal microflora and a major cause of severe endogenous infections (11). The staphylococcal cell wall determines several key aspects of the infection process, such as adherence (11,28), immune recognition (13), and resistance to host defenses (21,22).…”

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confidence: 99%

“…The staphylococcal cell wall determines several key aspects of the infection process, such as adherence (11,28), immune recognition (13), and resistance to host defenses (21,22). While many adhesive surface proteins have been investigated (12), the structure, function, and variability of nonproteinaceous polymers, such as peptidoglycan (PG) or teichoic acids, have remained parts of a neglected field of research.…”

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confidence: 99%

Muropeptide Modification-Amidation of Peptidoglycand-Glutamate Does Not Affect the Proinflammatory Activity ofStaphylococcus aureus

et al. 2007

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Peptidoglycan muropeptides, potent proinflammatory components, are amidated in Staphylococcus aureus for unknown reasons. To study whether this modification may modulate proinflammatory capacity, cytokine induction by isogenic S. aureus strains with different amidation levels and by synthetic amidated/nonamidated muramyldipeptides was evaluated. However, amidation did not significantly affect cytokine induction. This finding contributes to defining peptidoglycan receptor specificities and indicates that further rationales for muropeptide amidation have to be considered.Staphylococcus aureus is a frequent constituent of human nasal microflora and a major cause of severe endogenous infections (11). The staphylococcal cell wall determines several key aspects of the infection process, such as adherence (11, 28), immune recognition (13), and resistance to host defenses (21,22). While many adhesive surface proteins have been investigated (12), the structure, function, and variability of nonproteinaceous polymers, such as peptidoglycan (PG) or teichoic acids, have remained parts of a neglected field of research. S. aureus is known to modify the canonical PG structure by O acetylation of the glycan strand and by amidation of the ␣-carboxyl group of the D-glutamate (D-Glu) residue in muropeptides, resulting in the formation of D-isoglutamine (16, 29). While O acetylation confers lysozyme resistance (3), the primary role of D-Glu amidation has remained unclear. Nevertheless, the latter modification is known to affect the level of methicillin resistance (4, 17) and to contribute to vancomycin susceptibility in S. aureus (8). The amino group for D-Glu amidation in S. aureus muropeptides is most probably derived from free glutamine (17, 23). However, the responsible transamidase enzyme has not yet been identified. Gustafson et al. described a femC mutant with 48% decreased muropeptide amidation (17, 26). The femC mutant has a disrupted glnR gene encoding the regulator of the glutamine synthetase (Fig. 1A), which results in reduced glutamine synthetase activity. As a consequence of lower amounts of the amino group donor, muropeptide amidation is reduced in this mutant (17).PG has potent proinflammatory properties (5). It is sensed by the human innate immune system via NOD1 or NOD2 proteins (15,18). An additional role of the TLR2 receptor in PG sensing has been described previously (10) but remains a matter of debate (27). The minimal structure required for NOD1 recognition is a dipeptide consisting of D-Glu and meso-diaminopimelate (mesoDAP), which is mainly produced by gram-negative bacteria (14, 15). D-Glu amidation (leading to D-isoglutamine) strongly impairs PG recognition by NOD1 (7), and the amidation of mesoDAP completely abrogates the ability of NOD1 to detect PG (15). NOD2 has a different substrate specificity as it requires a muramyldipeptide (MDP) composed of N-acetylmuramic acid, L-alanine, and D-Glu (Fig. 1B) (19,27). S. aureus PG is recognized by NOD2 but not by NOD1 since it contains L-lysine instead of meso-D...

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“…New mechanisms of resistance have resulted in the simultaneous development of resistance to several antibiotic classes creating very dangerous Multidrug-Resistant (MDR) bacterial strains, some also known as ''superbugs'' [7].…”

Section: Development Of New Antimicrobial Agents With Bactericidal Acmentioning

confidence: 99%

Approach to Optimise the Treatment of Bacterial Infections: Combined Antimicrobial Therapy with Enhancers of Innate Immunity

SF¹

2012

Clin Exp Pharmacol

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The Staphylococcus aureus “superbug”

Cited by 238 publications

References 28 publications

Growth-phase dependence of susceptibility to antimicrobial peptides in Staphylococcus aureus

Growth-phase dependence of susceptibility to antimicrobial peptides in Staphylococcus aureus

Muropeptide Modification-Amidation of Peptidoglycand-Glutamate Does Not Affect the Proinflammatory Activity ofStaphylococcus aureus

Approach to Optimise the Treatment of Bacterial Infections: Combined Antimicrobial Therapy with Enhancers of Innate Immunity

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