How Staphylococcus aureus adapts to its host.
Article: MRSA: the first half century[Show abstract] [Hide abstract]
ABSTRACT: Fifty years ago methicillin-resistant Staphylococcus aureus (MRSA) first revealed themselves to the medical community, having been described in a landmark article published in the British Medical Journal. Among other things, their discovery set off a major response from the scientific and medical professions to control or even eliminate them as major human pathogens. Despite these efforts, however, MRSA have spread throughout the world and a half century after they burst upon the scene they continue to pose major challenges to research scientists and clinicians alike. In a very real sense, this year marks the 'birthday' of a remarkably successful pathogen. The major reasons for the ability of MRSA to prosper and cause disease in settings inimical to its survival form the basis of this article.Journal of Antimicrobial Chemotherapy 01/2012; 67(1):4-11. DOI:10.1093/jac/dkr437 · 5.44 Impact Factor
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ABSTRACT: CP (capsular polysaccharide) is an important virulence factor during infections by the bacterium Staphylococcus aureus. The enzyme CapF is an attractive therapeutic candidate belonging to the biosynthetic route of CP of pathogenic strains of S. aureus. In the present study, we report two independent crystal structures of CapF in an open form of the apoenzyme. CapF is a homodimer displaying a characteristic dumb-bell-shaped architecture composed of two domains. The N-terminal domain (residues 1-252) adopts a Rossmann fold belonging to the short-chain dehydrogenase/reductase family of proteins. The C-terminal domain (residues 252-369) displays a standard cupin fold with a Zn2+ ion bound deep in the binding pocket of the β-barrel. Functional and thermodynamic analyses indicated that each domain catalyses separate enzymatic reactions. The cupin domain is necessary for the C3-epimerization of UDP-4-hexulose. Meanwhile, the N-terminal domain catalyses the NADPH-dependent reduction of the intermediate species generated by the cupin domain. Analysis by ITC (isothermal titration calorimetry) revealed a fascinating thermodynamic switch governing the attachment and release of the coenzyme NADPH during each catalytic cycle. These observations suggested that the binding of coenzyme to CapF facilitates a disorder-to-order transition in the catalytic loop of the reductase (N-terminal) domain. We anticipate that the present study will improve the general understanding of the synthesis of CP in S. aureus and will aid in the design of new therapeutic agents against this pathogenic bacterium.Biochemical Journal 02/2012; 443(3):671-80. DOI:10.1042/BJ20112049 · 4.78 Impact Factor
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ABSTRACT: Staphylococcus aureus necrotizing pneumonia is a life-threatening disease that is frequently preceded by influenza infection. The S. aureus toxin Panton-Valentine leukocidin (PVL) is most likely causative for necrotizing diseases, but the precise pathogenic mechanisms of PVL and a possible contribution of influenza virus remain to be elucidated. In this study, we present a model that explains how influenza virus and PVL act together to cause necrotizing pneumonia: an influenza infection activates the lung epithelium to produce chemoattractants for neutrophils. Upon superinfection with PVL-expressing S. aureus, the recruited neutrophils are rapidly killed by PVL, resulting in uncontrolled release of neutrophil proteases that damage the airway epithelium. The host counteracts this pathogen strategy by generating PVL-neutralizing antibodies and by neutralizing the released proteases via protease inhibitors present in the serum. These findings explain why necrotizing infections mainly develop in serum-free spaces (eg, pulmonary alveoli) and open options for new therapeutic approaches.The Journal of Infectious Diseases 07/2012; 206(7):1138-48. DOI:10.1093/infdis/jis468 · 5.78 Impact Factor