1.

Introduction1.1 Staphylococcusaureus and its clinical relevanceStaphylococci are Gram-positive bacteria that belong to firmicutes. Theyhave sizes ranging from 0.5 ?m to 1.5 ?m in diameter and they can exist assingles, pairs or chains of 3 or 4 cells and irregularlyshaped clusters (Götz et al., 2006).

Staphylococciare facultative anaerobes where they can undergo both aerobic respiration aswell as fermentation (Harris et al., 2002).They are non-motile, non-spore forming bacteria that are resistant to heat andhigh salt concentration. Staphylococci are either coagulase positive orcoagulase negative depending on their ability to produce coagulase (Harris et al.

, 2002).Coagulase activates a glycoprotein in blood called pro-thrombin which in turn activatesfibrinogen into cross-linking fibrin clot (McAdow et al., 2012).Staphylococcus aureus is a coagulase-positive staphylococci whose namederives from the ancient Greek word “aurum” that means golden referring to itscolor of colonies when grown on solid medium (Harris et al., 2002).S. aureus colonizes primarily in nostrils of human population.

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It canalso colonize damaged skin and mucous membranes (Lowy,1998). Approximately20% of human population are persistent carriers of S. aureus while,about 30% are intermediate carriers and the rest of the human population arenever colonized (Wertheim et al., 2004).

Nasalcolonization is asymptomatic, but it is a major risk factor for subsequentinfections later on which range from soft tissue, minor skin and respiratoryinfections to life threatening necrotizing pneumonia, sepsis and Toxic Shock Syndrome (TSS)(Otto 2012) (DeLeo et al., 2010).A major growing burden to the worldwide health system is the emergence ofantibiotic-resistant S.

aureus strains in the recentyears due to the excessive and misuse of antibiotics. The first antibiotic ‘penicillin’was clinically used in 1940, but penicillin resistant S.aureus emerged after 2 years (Rammelkamp et al.

, 1942). Then,a penicillin-derived new semi-synthetic antibiotic ‘methicillin’ was introducedin 1959 but methicillin resistant S. aureus (MRSA) were detected after only1 year and nowadays, it is spread world-wide as both hospital acquired andcommunity acquired MRSA (Otto 2012). Based on theNational Nosocomial infections surveillance (NNIS) system in USA in 2004, morethan 60% of S. aureus isolatesfrom ICUs of USA hospitals were MRSA. Vancomycinantibiotic is a therapeutic resort that is used for the treatment of infectionstriggered by MRSA strains.

However, in 1996 MRSA strains with vancomycinintermediate resistance (VISA) were identified and later in 2000s the firstvancomycin-resistant S. aureus strains(VRSA) were reported (Appelbaum 2006).    1.2 StringentresponseStringentresponse is a conserved global regulatory process that occurs in most bacteria under stress conditions. It was firstdemonstrated in E.coli 1969 by Cashel and Gallant through the use ofradioactive nucleotides and thin layer chromatography, they reported thepresence of the so-called ‘magic spots’ under conditions of nutrientlimitation, particularly amino acid starvation (Cashel 1969).

 The so-called ‘magic spots’ were lateridentified to be Guanosine tetra phosphate (ppGpp) and Guanosine pentaphosphate(p)ppGpp, collectively known as alarmones (p)ppGpp figure (1.1). Alarmones re-organize cellulartranscriptional activities and gene metabolism leading to adaptation to stress conditions through variety of processes such asslow bacterial growth, inhibition of DNA replication, activation/repression ofsome genes.  Figure (1.1) chemical structure of Guanosine penta phosphate (left) and Guanosine tetra phosphate (right) (Miller 2013).              In E. coli, the level of alarmones isregulated by two enzymes: RelA and SpoT (Carneiro et al.

, 2011). RelA is responsible for the synthesis ofalarmones in conditions of amino acid starvation that is detected through arrivaluncharged tRNA in the Acceptor site (A site) of the ribosome (Haseltine andBlock 1973). RelA has a synthetase domain which catalyzes the pyrophosphorylationof GTP or GDP -using ATP as pyrophosphate donor- into pppGpp and ppGpprespectively (Haseltine and Block 1973). SpoT isresponsible for manganese-dependent degradation of alarmones which is crucialto avoid toxic accumulations of alarmones in the cell in presence of active RelA(Xiao et al.

, 1991). SpoT has ahydrolase domain that removes the pyrophosphate group from (p)ppGpp producingGTP or GDP. In addition, SpoT has a weaksynthesis activity in response to iron, carbon and fatty acid starvation. Itdetects fatty acid starvation through the interaction of acyl carrier protein(ACP) with a conserved domain called TGS in its C-terminal part (Xiao etal., 1991) (Battesti and Bouveret 2006).