Site Loader

ABSTRACT
Antibiotics
were ceaselessly used to treat bacterial infections and their
constant use has developed high degree of resistance in bacteria.
Methicllin resistant staphylococcus
aureus (MRSA)
is one among such potent bacteria that has been a great concern in
almost all areas of medicine. They almost halted the golden era of
antibiotics.
MRSA
has been the reason for most of community acquired infections and
hospital acquired infections. The presence of a mutant in the
bacteria makes it resistant against most of the antibiotics.
Because
of
the lack of treatment and expanded death rate there is a requirement
for a potent therapy to convey an end to this bacterial infection.

KEY
WORDS
MRSA,
Staphylococcus aureus, ?-lactam antibiotics, Penicillin binding
proteins, Curcumin

We Will Write a Custom Essay Specifically
For You For Only $13.90/page!


order now

INTRODUC`TION

Methicillin
resistant staphylococcus aureus is a gram positive bacteria and an
antibiotic resistant strain of staphylococcus aureus. It has been
found to be one of the reasons for nosocomial infections. In 1972 it
was from mastitic infected cattle MRSA was first isolated. Animals
and humans are mostly infected by these bacteria. The infections
include rashes, oesteomyelitus, septicaemia and pneumonia. This
strain of S.aureus has become a worldwide threat due to lack of
treatment against this bacteria. National nosocomial infection
surveillance system shows that S.aureus is the most common cause for
nosocomial pneumonia and one of the causes for bloodstream infections
in USA. In USA the mortality rate of different diseases like AIDS,
MRSA infection, hepatitis and tuberculosis were compared and
interestingly it was found that the mortality rate was found to be
more for MRSA infections. The prevalence rate for MRSA infections in
developed countries were found to be: UK (44%), Japan (60-70%), USA
(>50%). But 2011 reports shows that the mortality rate in USA has
declined due to proper hospital care management. The bacterium is
resistant to ?- lactam antibiotics like penicillin, methicillin,
erythromycin etc. Their resistance to antibiotics is due to the
presence of mecA and mecC gene. MecA gene plays a major role in the
production of penicillin binding protein 2a (PBP2a). PBPs are
membrane bound enzymes that helps in catalyzation of transpeptide
reaction which is needed for the cross-linkage of peptidoglycan
chains. Due to low affinity of PBPs to ?-lactam antibiotics,
staphylococcus aureus can withstand high concentrations of these
antibiotics. In some MRSA strains the resistance is mainly influenced
by a group of genes called ‘blaz’. Another series of genes known
as fem genes also plays an essential role in resistance to meticillin
by cross linking peptidoglycan strands. The recent studies shows that
the MRSA were resistant towards methicillin(45.9%), cefixame(44%),
co-trimoxazole(28%),erthyromycin(28%), gentamycin (18%). But 100%
were sensitive to vancomycin(glycopeptide). Need of discovery for new
antibiotics become important when vancomycin resistant MRSA was
isolated in 1996 from Japan. Linezolid is one of the synthetic
antibiotics used recently for the treatment. They act by destroying
the bacterial growth by inhibiting the initiation process in protein
synthesis. Linezolid also helps in inhibiting virulence factor
expression and reduces the amount of poison produced by gram positive
pathogens. Studies have shown that drugs against MRSA should be
protein synthesis inhibitors with a gram positive spectrum, eg:
quinupristin, dalfopristin. Studies have shown that MRSA has been
acquired from hospital care workers who have poor handwashing
techinques. So these conditions can be minimised by improving hand
washing techniques. MRSA can be controlled by identifying their
colonies or the persons who are infected by it. Active Detection and
Isolation (ADI) (which include screening high risk patients for MRSA,
taking precaution for those who are MRSA positive, adopting proper
hand hygiene techniques) can be used as a controlling technique for
MRSA infections.

ANTIBIOTIC
ACTION
The
discovery of penicillin by Alexander Fleming opened the door for
other antibiotics to the world. Antibiotic used to treat various
diseases has specific site for its action. In the recent world
majority of diseases has been cured with the antibiotics, this lead
to the detailed study about this class of drugs. They are classified
on the basis of mechanism
of action, chemical structure, or spectrum of activity. They act by
inhibiting cell growth leading to lysis of cell.
Classification on the basis of mechanism of action as follows:
CELL
WALL GROWTH INHIBITORS
The
following class of drugs acts by this mechanism: ?-lactam
antibiotics, glycopeptides, bacitracin
a)
?-LACTAM ANTIBIOTICS:
Eg:
pencillins and cephalosporins
Mechanism
of action:
Major
component of cell wall comprises of peptidoglycans1. The
peptidoglycans are made of N-acetyl glucosamine and N-acetyl muramic
acid. The n-acetyl muramic acid unit contain peptide chains which are
the site of crosslinking. The S.aureus contains pentapeptide chains
of L-Ala-?-D-Glu-L-Lys (Gly) 5-D-Ala-D-Ala 2. These are produced
within the cell but the cross linking takes place outside the cell.
The cross linking is done by a group of enzymes known as
transpeptidases. These classes of Enzymes are called Penicillin
Binding Proteins (PBP).They are bifunctional enzymes having both
transpeptidase domain and transglycosylase domain. The
transglycosylase domain of the enzyme helps in the extension of the
sugar by the addition of new peptidioglycan units from
N-acetylglucosamine-b-1,
4-N-acetylmuramyl-pentapeptide-pyrophosphoryl-undecaprenol
1. The transpeptidases perform their activity by acylation using
serine as their active site 3. The ?-lactam antibiotics act on
these enzymes. They form covalent pencilloyl complex which prevents
the cross linking reactions and their by inhibiting the cell wall
synthesis.
b)
GLYCOPEPTIDES
Eg
: vancomycin,
Mechanism
of action: It targets D-Ala-D-Ala terminal of cell wall
(peptidoglycan chain) inhibiting the transpeptidase activity. Thus
they prevent the cross linking of peptidoglycans which results in
poor cell wall synthesis. The resistance can arise by increasing the
thickness of cell wall. Vancomycin binds to the D-ala-D-ala terminal
through five hydrogen bonds. This results in high affinity of
antibiotics to its target but production of D-ala-D-lac lead to
resistance against the site.
c)
BICITRACIN
They
interfere with dephosphorylation of C55-isoprenyl
pyrophosphate which is a membrane carrier molecule that transports
the building blocks of bacterial cell wall. It also acts as a
receptor in plasma membrane of bacteria.

NATURE
OF RESISTANCE

Wide
spread of MRSA has made an interest on identifying the mechanism of
resistance of S.aureus against different antibiotics. It has been
reported that most of the antibiotics used to treat MRSA have
acquired resistance against its action. ?– lactam antibiotics
which have greater onset of action against the infection and so this
class of drugs (penicillin, erythromycin) was used. Methicillin is no
longer used due to its nephrotoxicity, yet the staphylococcus aureus
resistant to cloxacillin or nafcillin are refered as methicillin
resistant organism. The action of ?–lactam antibiotics is due to
the presence of Penicillin Binding Protein (PBP) in the cell wall of
bacteria which have affinity over ?–lactam antibiotics covalently
4. The key role of ?–lactam antibiotics is that it acts as
substrate analogues for PBPs which helps in catalyzing
transpeptidation. Most of the clinically obtained MRSA contain a
staphylococcal origin gene mecA coding 72kd PBP2a having affinity
towards ?-lactam ring 1. General assumption has made that mecA
gene act as surrogate enzyme for synthesis of cell wall. MecA gene
have structural resemblance of cell wall synthesizing transpeptidase.
A bacterial cell wall is composed of repeating units of disaccharides
which include N- acetyl glucosamine and N- acetyl muramic acid. The
N-acetyl muramic acid is modified by pentapeptides which is one of
the differentiating factor in gram positive and gram negative
bacteria. The peptidoglycan is produced inside the cell but their
crosslinking takes place outside the cell membrane. Transpeptidases
are the enzymes which does this function. After the cross-linking a
peptide bond is formed between D-alanine group of one chain with the
L-lysine group of the other. Transpeptidases enzyme uses an active
serine and performs their function by acylation. This is the site
where ?-lactam antibiotics act to produce their effect. They inhibit
the transpeptidases enzyme thereby preventing the cross-linking of
peptidoglycans. The transpeptidase enzyme forms a strong covalent
bond with the antibiotics and thereby prevents the further reactions.
Since the S.aureus has attained resistance over this mechanism mecA
gene takes over the step of cell wall synthesis. This leads to the
investigation for other site to fight against the resistance.

Post Author: admin

x

Hi!
I'm Sonya!

Would you like to get a custom essay? How about receiving a customized one?

Check it out