1. glycoprotein in blood called pro-thrombin which in

1. Introduction

1.1 Staphylococcus
aureus and its clinical relevance

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Staphylococci are Gram-positive bacteria that belong to firmicutes. They
have sizes ranging from 0.5 ?m to 1.5 ?m in diameter and they can exist as
singles, pairs or chains of 3 or 4 cells and irregularly
shaped clusters (Götz et al., 2006).Staphylococci
are facultative anaerobes where they can undergo both aerobic respiration as
well as fermentation (Harris et al., 2002).
They are non-motile, non-spore forming bacteria that are resistant to heat and
high salt concentration. Staphylococci are either coagulase positive or
coagulase negative depending on their ability to produce coagulase (Harris et al., 2002).
Coagulase activates a glycoprotein in blood called pro-thrombin which in turn activates
fibrinogen into cross-linking fibrin clot (McAdow et al., 2012).
Staphylococcus aureus is a coagulase-positive staphylococci whose name
derives from the ancient Greek word “aurum” that means golden referring to its
color of colonies when grown on solid medium (Harris et al., 2002).
S. aureus colonizes primarily in nostrils of human population. It can
also colonize damaged skin and mucous membranes (Lowy,
1998). Approximately
20% of human population are persistent carriers of S. aureus while,
about 30% are intermediate carriers and the rest of the human population are
never colonized (Wertheim et al., 2004). Nasal
colonization is asymptomatic, but it is a major risk factor for subsequent
infections later on which range from soft tissue, minor skin and respiratory
infections 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 of
antibiotic-resistant S. aureus strains in the recent
years 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 introduced
in 1959 but methicillin resistant S. aureus (MRSA) were detected after only
1 year and nowadays, it is spread world-wide as both hospital acquired and
community acquired MRSA (Otto 2012). Based on the
National Nosocomial infections surveillance (NNIS) system in USA in 2004, more
than 60% of S. aureus isolates
from ICUs of USA hospitals were MRSA. Vancomycin
antibiotic is a therapeutic resort that is used for the treatment of infections
triggered by MRSA strains. However, in 1996 MRSA strains with vancomycin
intermediate resistance (VISA) were identified and later in 2000s the first
vancomycin-resistant S. aureus strains
(VRSA) were reported (Appelbaum 2006). 




1.2 Stringent

response is a conserved global regulatory process that occurs in most bacteria under stress conditions. It was first
demonstrated in E.coli 1969 by Cashel and Gallant through the use of
radioactive nucleotides and thin layer chromatography, they reported the
presence of the so-called ‘magic spots’ under conditions of nutrient
limitation, particularly amino acid starvation (Cashel 1969).  The so-called ‘magic spots’ were later
identified to be Guanosine tetra phosphate (ppGpp) and Guanosine pentaphosphate
(p)ppGpp, collectively known as alarmones (p)ppGpp figure (1.1). Alarmones re-organize cellular
transcriptional activities and gene metabolism leading to adaptation to stress conditions through variety of processes such as
slow bacterial growth, inhibition of DNA replication, activation/repression of
some 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 is
regulated by two enzymes: RelA and SpoT (Carneiro et al., 2011). RelA is responsible for the synthesis of
alarmones in conditions of amino acid starvation that is detected through arrival
uncharged tRNA in the Acceptor site (A site) of the ribosome (Haseltine and
Block 1973). RelA has a synthetase domain which catalyzes the pyrophosphorylation
of GTP or GDP -using ATP as pyrophosphate donor- into pppGpp and ppGpp
respectively (Haseltine and Block 1973). SpoT is
responsible for manganese-dependent degradation of alarmones which is crucial
to avoid toxic accumulations of alarmones in the cell in presence of active RelA
(Xiao et al., 1991). SpoT has a
hydrolase domain that removes the pyrophosphate group from (p)ppGpp producing
GTP or GDP. In addition, SpoT has a weak
synthesis activity in response to iron, carbon and fatty acid starvation. It
detects fatty acid starvation through the interaction of acyl carrier protein
(ACP) with a conserved domain called TGS in its C-terminal part (Xiao et
al., 1991) (Battesti and Bouveret 2006).