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InFirmicutes such as S. aureus and Bacillus subtilis,alarmones don’t directly bind to RNAP and there is no DksA co-factor (Krasny et al., 2004). Instead, many genes are indirectlyregulated through the loweringof GTP pool that accompanies alarmone production.

In B. subtilis, ribosomal promoters initiate with GTPwhich is the transcription-initiating nucleotide (iNTP)and therefore, Low GTP pool that occurs in stringent response leads toinhibition rRNA promoters ( Krásný et al., 2004) (Krásný et al., 2008). Also in S. aureus,ribosomal genes such as rpsL (encodingfor ribosomal protein S2) are repressed under stringent conditions due to lowGTP pool (Geiger etal., 2010).Moreover,alarmones can indirectly affect gene expression through CodY repressor.

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In B.subtilis, CodYis activated by GTP under normal conditions and represses genes having CodYconserved motif through inhibition of RNAP (Handke et al., 2008).Under stringent conditions, CodY is not activated since there is a decrease inthe level of GTP. Therefore, it does not bind to its conserved motif on DNAleading to de-repression (activation) of CodY-dependent genes (Shiverset al.

, 2004). In S.aureus, CodY repressor is activated by GTP in addition to branched chainamino-acids leading to repression of genes such as virulence genes and genesinvolved in transport and metabolism of amino acids and nitrogen. In stringentresponse, low GTP pool and the descent of level branched chain amino-acidsleads to activation of CodY regulated genes in S.

aureus (Pohl et al., 2009) as illustrated in Figure (1.5).   Figure (1.5) Scheme of the role of CodY repressor in S. aureus under nutrient rich conditions (left) and nutrient limitation (right). Under nutrient rich conditions, there are high levels of GTP and BCAA which bind and activate CodY repressor.

CodY binds to its conserved CodY box on DNA and inhibits RNAP leading to repression of genes. Under nutrient limitation, there is low level of BCAA. In addition, RSH is activated and synthesizes (p)ppGpp leading to a decrease in the level of GTP. CodY does not bind to its motif leading to activation of genes required for stringent response (Geiger et al.

, 2014).                   When S. aureus is treated withMupirocin, (p)ppGpp are synthesized with the induction of transcriptionalchanges similar to those occurring in isoleucine depletion (Geiger et al., 2010).Mupirocin is a potent antibiotic which mimics isoleucine starvation throughinhibition of bacterial isoleucyl tRNA synthetase. Mupirocin is astructural analogue of isoleucyl-adenylate (Ile-AMP) where it competes with Ile-AMPon binding sites of isoleucyl tRNA synthetases.

Therefore, mupirocin leads tothe accumulation of uncharged isoleucyl –tRNAs which is a signal of amino-aciddepletion in the cell that activates the stringent response (Nakama et al., 2001) (Reiß et al., 2011). 1.

4 Protein-Protein InteractionsInteractions seem to play an important role for the correct functionof RSH. It was shown that in E. coli, interactionsare crucial for regulating the activity of RelA where it is active in a monomericstate and inactive in an oligomeric state. In addition, it was shown that theC-terminal domain is the part involved in RelA-RelA interactions (Gropp et al., 2005).

Furthermore, RelMtb which is abifunctional RelA/SpoT homologue in Mycobacterium tuberculosis wasreported to form trimers and the removal of theC-terminal part results in a monomeric state indicating its essentiality formultimerization. It was also shown that the trimer state is less active thanmonomer state indicating that interactions affect the enzyme functionality (Avarbock et al., 2005). However, protein-protein interactions between RSHfrom S. aureus have not been tested before.   1.5  S.

aureusresistance to oxidative stressBacteria can encounter oxidative stress endogenously (inside the bacteria)or exogenously (from an outside source). Endogenous oxidative stress can takeplace during bacterial aerobic respiration and intracellular redox reactions.In aerobic respiration, oxygen is the final electron acceptor where it iscompletely reduced forming H2O.

Sometimes, incomplete reduction ofoxygen takes place when oxygen interacts with reduced FAD cofactor leading togeneration of reactive oxygen species (ROS) such as superoxide anion (O2?)and hydrogen peroxide (H2O2) (Massey et al., 1969)(Korshunov et al., 2010).In addition, iron in ferrous form(Fe2+)can react with H2O2 generating hydroxyl radicals (HO•) in areaction called Fenton reaction (Imlay et al., 1988)(Repine et al., 1981). In addition to endogenous oxidative stress, S.

aureus encounters exogenous oxidativestress through host innate immune cells as macrophages and neutrophils. Theseimmune cells have NADPH oxidase enzyme (NOX) which reduces oxygen into O2?in oxidative burst. Dismutation of O2?cantake place generating H2O2 which can be further convertedby myeloperoxidase enzyme into cytotoxic hypochlorite ion (OCl-) (Pandayet al., 2014)(Harrison etal., 1976).Moreover, immune cells can produceNitric oxide (•NO) which is a cytotoxic reactiveoxidant. •NO can further react with O2? producingperoxynitrite (OONO?)which is a highly reactive bactericidal compound (Huieand Padmaja, 1993). ROS and nitrosativestressors damage bacterial DNA and proteins.

An illustration of the oxidativestressors to S. aureus is shown in figure(1.6).

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