Gram-positive pathogens

Staphylococcus aureus causes a number of community- and hospital derived infections ranging from uncomplicated wound infections to severe diseases as septicemia or endocarditis. S. aureus expresses a large number of proteins that specifically impair the effectiveness of the innate immune system. These include factors that modulate antimicrobial peptides and plu ocytic cells but also complement modulators (Table 1). The first anti-opsonic molecule identified in S. aureus was Staphylococcal protein A (SpA) (42 kDa), a surface protein that can also be released in the extracellular milieu. By binding the Fc part of G molecules, SpA covers the bacterial surface with G molecules in a manner that prevents recognition by Fc-receptors on phi ocytes. This way, SpA blocks Fc-receptor mediated ph ocytosis. Furthermore, since SpA interferes with C Iq binding it prevents classical pathway complement fixation as welL  

The staphylococcal cell wall-associated protein Sbi (45 kDa) is also involved in immunoglobulin binding. The Sbi extracellular region (Sbi-E) consists of four imqor domains including two G-binding regions. Recent data have indicated that the other two domains have 

Another way for S. aureus to inhibit phagocytosis is via the production of Staphylokinase (SAK) (16 kDa). SAK targets plasminogen (PLG) on the bacterial sur ce and activates it into plasmin (PL). PL can cleave two major opsonic molecules, IgG (at the hinge region) and C3b. It was shown that the conversion of PLG to PL by SAK leads to removal of IgG and C3b on the bacterial surface. Thus, SAK impairs both IgG and complement dependent phagocytosis by human neutrophils.  

Staphylococcal superant en-like (SSL) protein 7 is a 23 kDa protein that belongs to a family of 11 different SSLs that are clustered on staphylococcal pathogenicity island 2 (Sapln2). SSL7 binds to %A but also prevents formation of the MAC via specific binding to C5. SSL7 binding to C5 possibly also prevents formation of C5a which seems more important for clearance of S. aureus because its thick cell wall renders it resistant to MAC-mediated lysis. 

The importance fi r inhibidng C5a-mediated responses -was already indicated by the Chemotaxis inhibitory protein of S. aureus (CHIPS) (14 kDa). This extracellular protein binds two major chemotactic receptors on neutrophils, the C5a receptor (C5aR) and the formyl peptide receptor (FPR). By binding these receptors, CHIPS efiectively blocks neutrophil chemotaxis towards C5a and formylated peptides (e.g., fMet-Leu-Phe) (fMLP). 

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The discovery and biological properties of lincomycin (1, R = OH, R = H) were described ia 1962 (1). This antibiotic is active in vitro and in vivo against most of the common gram-positive pathogens. Resistance by Staphylococci is developed slowly ia a stepwise manner, based on in vitro serial subculture experiments, and its activity is not iafluenced by body fluids up to concentrations of 50% ia the assay medium (2). 

Vancomycin is used frequently in severe infections with gram-positive pathogens. With increasing staphylococcal resistance, linezolid, quinupris-tin/dalfopristin, daptomycin, and tigecycline are alternatives. 

Straus SK, Hancock RE. (2006) Mode of action of the new antibiotic for Gram-positive pathogens daptomycin Comparison with cationic antimicrobial peptides and lipopeptides. Biochim BiophysActa 1758 1215-1223. 

A novel cyclic lipopeptide antibiotic was isolated from cultures of Strep-tomyces roseosporus grown in the presence of decanioc acid. Daptomycin interacts with the bacterial cell membrane and interferes with membrane potential.Unlike polymyxin B, daptomycin can target majority of clinically relevant Gram-positive pathogens. 

Carpenter CF, Chambers HF Daptomycin Another novel agent for treating infections due to drug-resistant gram-positive pathogens. Clin Infect Dis 2004 38 994. [PMID 15034832]... 

Hancock RE Mechanisms of action of newer antibiotics for gram-positive pathogens. Lancet Infect Dis 2005 5 209. [PMID 15792738]... 

The addition of either the fluorine or the piperazino moiety, or both, to the basic quinolone backbone enhances the overall antibacterial activity of the new compounds. Fluorine increases the activity against gram-positive pathogens,... 

Novobiocin (Fig. 3.9) is a narrow-spectrum antibiotic with antibacterial activity against many gram-positive pathogens. It is frequently used, in combination with penicillin, for treatment of bovine mastitis by intramammary infusion of 200 mg/ quarter in two quarters, and to control fowl cholera and staphylococcal infections in chickens and turkeys at a level of 200-350 g/ton in feed. 

Lode HM (2009) Clinical impact of antibiotic-resistant Gram-positive pathogens. Clin Microbiol Infect 15 212-217... 

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