9 CHAPTER-2 REVIEW OF LITERATURE In this chapter an attempt has been made to review the work done on the identification of traditional medicinal plants of Himachal Pradesh and characterization of plant derived compounds that exhibit synergism with commercial antibiotics against clinical pathogenic bacteria. Due to paucity of literature available on Colebrookea oppositifolia, studies on other plants have been incorporated in order to find synergism. The literature is reviewed under following aspects: 2.1 Antibiotics and their mode of actions 2.2 Drug resistance and mechanism of resistance 2.3 Importance of traditional medicinal plants 2.4 Historical uses of essential oils and terpenoids 2.5 Synergistic effect of medicinal plants and antibiotics 2.6 Characterization of phytochemicals 2.1 ANTIBIOTICS AND THEIR MODE OF ACTIONS Understanding the role of microorganisms in disease took many years for scientists to establish the connection between microorganisms and illness. Robert Koch, for the first time demonstrated the role of bacteria Bacillus anthracis causing disease anthrax; later Louis Pasteur and Robert Koch observed that airborne Bacillus led into the inhibition of Bacillus anthracis to which they gave the name antibiosis in 1877. The term was renamed by Selman Waksman into antibiotics in 1942 and has been defined as a chemical substance derivable from microorganisms or produced by chemical synthesis to kill or inhibit the microorganisms and cure infections. Antibiotics have been classified into three categories derived from various sources; 1) Natural antibiotics: derived from fungus e.g. benzylepenicillin and gentamycine; 2) Semi-synthetic antibiotics are chemically-altered natural compounds e.g. ampicillin and amilkacin; 3) Synthetic antibiotics are chemically designed in laboratories e.g. moxifloxacin and norfloxacin. The antibiotics work with two phenomenons; 1) Inhibition of microbial multiplication known as bacteriostatic effect; 2) By killing the microbial population known as bactericidal effect. The characteristic feature of an antibiotic for prescription is taken into the
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CHAPTER-2 REVIEW OF LITERATURE - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/43073/1... · Figure 2.7: Chemical structures of tetracyclines and chloramphenicol: A) Tetracyclines
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CHAPTER-2
REVIEW OF LITERATURE
In this chapter an attempt has been made to review the work done on the identification
of traditional medicinal plants of Himachal Pradesh and characterization of plant derived
compounds that exhibit synergism with commercial antibiotics against clinical pathogenic
bacteria. Due to paucity of literature available on Colebrookea oppositifolia, studies on other
plants have been incorporated in order to find synergism. The literature is reviewed under
following aspects:
2.1 Antibiotics and their mode of actions
2.2 Drug resistance and mechanism of resistance
2.3 Importance of traditional medicinal plants
2.4 Historical uses of essential oils and terpenoids
2.5 Synergistic effect of medicinal plants and antibiotics
2.6 Characterization of phytochemicals
2.1 ANTIBIOTICS AND THEIR MODE OF ACTIONS
Understanding the role of microorganisms in disease took many years for scientists to
establish the connection between microorganisms and illness. Robert Koch, for the first time
demonstrated the role of bacteria Bacillus anthracis causing disease anthrax; later Louis
Pasteur and Robert Koch observed that airborne Bacillus led into the inhibition of Bacillus
anthracis to which they gave the name antibiosis in 1877. The term was renamed by Selman
Waksman into antibiotics in 1942 and has been defined as a chemical substance derivable from
microorganisms or produced by chemical synthesis to kill or inhibit the microorganisms and
cure infections. Antibiotics have been classified into three categories derived from various
sources; 1) Natural antibiotics: derived from fungus e.g. benzylepenicillin and gentamycine; 2)
Semi-synthetic antibiotics are chemically-altered natural compounds e.g. ampicillin and
amilkacin; 3) Synthetic antibiotics are chemically designed in laboratories e.g. moxifloxacin
and norfloxacin. The antibiotics work with two phenomenons; 1) Inhibition of microbial
multiplication known as bacteriostatic effect; 2) By killing the microbial population known as
bactericidal effect. The characteristic feature of an antibiotic for prescription is taken into the
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account in such a way that it should be selective target, bactericidal, narrow spectrum so that it
does not kill the normal gut flora, high therapeutic index, few adverse effects, various route of
administration, good absorption and emergence of resistance is low.
Antibiotics work with different mode of action and have been classified according to their
properties;
1. Inhibitors of cell wall synthesis: The various classes of antibiotics which comes under
this category are;
A. β- lactams: it is the part of core structure of several antibiotics families like
penicillins, cephalosporins, carbapenems and monobactams. They generally work as
inhibitor of cell wall biosynthesis.
Figure 2.1: Chemical structures of β-lactam class antibiotics: A) Penicillin: These antibiotics
inhibit cross links in peptidoglycan in cell wall; B) Cephalosporins: They disrupt the synthesis of peptidoglycans; C) Carbapenems: They inhibit L,D-transpeptidases synthesis during cell synthesis in bacteria; D) Monobactams: They are genrally employed against aerobic Gram’s negative bacteria (Neisseria sp., Pseudomonas sp.)
A.1 Penicillin: There are wide range of antibiotics falling under this class for
example; a) Natural penicillin (Penicillin G): they do not produce β-lactamase; b)
Penicillinsase resistant penicillins (Methicillin); c) Extended-spectrum penicillins
(Aminopenicillins e.g. amoxicillin, carboxypenicillins and ureidopenicillins); d) β-
lactamase inhibitors, widely used antibiotics as they produce β-lactamase
(Amoxicillin+clavulanic acid, ampicillin+sulbactum and piperacillin + tazobactum).
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Figure 2.2: Chemical structures of various classes of penicillins: A) Chemical structure
of Penicillin G; B) Methicillin (Penicillinsase resistant penicillin); C) Amoxycillin (Aminopenicillins, Extended-spectrum penicillin); D) Amoxicillin and Clavulanic acid (β-lactamase inhibitors)
A.2 Cephalosporins: They are the inhibitors of cell wall synthesis in bacteria and
have been characterized as; A) 1st generation cepahlosoprins: A narrow spectrum
fight against Gram’s positive bacteria e.g. cefazolin; B) 2nd generation
cephalosporins: Better Gram’s negative bacteria coverage e.g. cefuroxime; C) 3rd
generation cephalosporins: Much active against Enterobacteriaceae and
Psuedomonas aeruginosa e.g. ceftriaxone; D) 4th generation cephalosporins: Broad
spectrum of cepahlaosporins against against Enterobacteriaceae and Psuedomonas
aeruginosa e.g. cefepime.
.
Figure 2.3: Chemical structures of various classes of cephalosporins: A) 1st generation
cephalosporins e.g. Cefazolin, mainly prescribed for bacterial infection of skin; B) 2nd generation cephalosporin e.g. Cefuroxime, widely used for various bacterial infection like against Haemophilus influenzae, Neisseria gonorrhoeae and Lyme disease; C) 3rd generation cephalosporin e.g. Ceftriaxone, widely used for the treatment of pneumonia, bacterial meningitis, skin infection, urinary tract infection etc.; D) 4th generation cephalosporins e.g. Cefepime used against Enterobacteriaceae and Psuedomonas aeruginosa
Figure 2.4: Chemical structures of carbapenem and monobactumstructure of meropenem (carbapenem), broad spectrum antibiotics used for Gram’s positive and negative bacteria; B) Chemical structure of aztreonam (monobactum), anitratus, Escherichia coli
B. Glycopeptides:They work as inhibitor of cell wall synthesis o
infection e.g. vancomycin.
C. Fosfomycins: They act
than the penicillin and cephalosporins.
Figure 2.5: Chemical structures of glycopeptides and fvancomycin (glycopeptides), widely used foS.aureus (MRSA) Chemical structure of fosfomycin, generally used for urinary tract infections
A
They are the β-lactams with broad spectrum antibiotics against
Monobactams: They generally act on Gram’s negative bacteria
(Enterobacteriaceae and Psuedomonas) e.g. aztreonam.
: Chemical structures of carbapenem and monobactum:structure of meropenem (carbapenem), broad spectrum antibiotics used for Gram’s positive and negative bacteria; B) Chemical structure of aztreonam (monobactum), used to treat bacterial infections caused by
Escherichia coli and Proteus mirabilis
They work as inhibitor of cell wall synthesis of Gram positive
ancomycin.
They act on the inhibition of cell wall synthesis at a stage earlier
than the penicillin and cephalosporins.
tructures of glycopeptides and fosfomycins: A) Chemical structure of vancomycin (glycopeptides), widely used for the treatment of methicillin
(MRSA) and multi-resistant Staphylococcus epidermidisChemical structure of fosfomycin, generally used for urinary tract infections
2. Inhibitors of protein synthesis: They generally bind to the RNA of 30S ribosomal
sub-unit which affects normal protein synthesis The various classes of antibiotics which
comes under this category are;
A. Aminoglycosides: They are bactericidal and broad spectrum killing both Gram’s
positive and Gram’s negative bacteria by inhibiting the protein synthesis which is
done by aminoglycosides, perturbing the protein elongation at 30S ribosomal
subunit leading into the inaccurate mRNA translation, hence, inaccurate translated
protein product is produced e.g. kanamycin, amikacin and gentamycin etc.
B. MLSK: They are macrolids, lincosamides, streptogramins and ketolides. They are
generally confined to the Gram’s positive bacteria. All four classes are of different
structure but same mode of action e.g. erythromycin, telithromycin, clindamycin
etc. They inhibit the protein synthesis as discussed above and also by
immunomodulation in diffuse panbronchiolitis (DBP).
Figure 2.6: Chemical structures of aminoglycosides (kenamycin A) and MLSK
(macrolide-lincosamide-streptogramin-ketolide) (erythromycin): A) Kenamycin interferes with 30S subunit of prokaryotic ribosomes inhibiting the protein synthesis; B) Erythromycin is the macrolid, which binds with 50S subunit of ribosomes and interfers with aminoacyl translocation inhibiting the protein synthesis
C. Tetracyclines: They are generally bacteriostatic and broad spectrum antibiotics
genrally act by inhibiting the binding of aminoacyl tRNA to mRNA-ribosome
complex.
D. Phenicols: They are also bacteriostatic as well as broad spectrum e.g.
chloramphenicol. They prevent the protein elongation by inhibiting the peptidyl
transferase activity.
A B
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Figure 2.7: Chemical structures of tetracyclines and chloramphenicol: A) Tetracyclines are the braod spectrum antibiotics used in urinary tract infections, respiratory tract infections and intestinal infections, especially prescribed for β-lactama and erythromycin allergic patients; B) Chloramphenicol is a broad spectrum antibiotic and used in treating ocular infections caused by a number of bacteria including Staphylococcus aureus, Streptococcus pneumoniae and Escherichia coli
E. Oxazolidinones: They are broad spectrum and narrow spectrum antibiotics e.g.
linezolid.
F. Ansamycins: Generally works on Gram’s positive bacteria and some Gram’s
negative bacteria e.g. rifamycin.
Figure 2.8: Chemical structures of Oxazolidinones and ansamycin (rifampicin): A) Oxazolidinones
are the inhibitor of protein synthesis and are widely used against gram-positive pathogens (Staphylococcus aureus, Enterococcus sp., and Streptococcus pneumoniae); B) Rifampicin, an antibiotic of ansamycin group, inhibits bacterial DNA-dependent RNA synthesis by inhibiting bacterial DNA-dependent RNA polymerase and widely used in the treatment of tuberculosis, MRSA etc.
3. Inhibitors of membrane function: They target on the membrane phospholipids
(lipopolysachharides and lipoproteins. The various categories are;
A. Polymyxins: They act as narrow spectrum for Gram’s negative bacteria by
disrupting the cell membrane after interacting with phospholipids present on the
B. Colistin: Colistin has poly-cationic regions and they interact with the bacterial outer
membrane due which displacement in bacterial counter ions in
the lipopolysaccharide occurs. solubilizing the membrane in an aqueous
environment.
Figure 2.9: Chemical structures of Polymyxins and Colistin: A) Polymyins, it contains a cyclic
peptide with longhydrophobic tail, which disrupt the bacterial cell membrane by interacting with phospholipids, typical use of drug is against multidrug resistant Psuedomonas aeroginosa and Enterobacteriaceae; B) Colistin, is a polymyxins antibiotics, effective against most Gram-negative bacilli (Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter)
4. Inhibitors of nucleic acid synthesis: They work as inhibitor of nucleic acid synthesis.
The various classes fall under this category are;
A. Quinolones: They target on DNA gyrase which is responsible for cutting one of
the chromosomal DNA strands at the beginning of the supercoiling process e.g.
ciprofloxacin, levofloxacin, gatifloxacin and moxifloxacin.
B. Furanes: They are broad spectrum and bactericidal drugs act on damaging
Figure 2.10: Chemical structures of Quinolones (ciprofloxacin) and Furanes (nitrofurantoin): A)
Ciprofloxacin, it is a second class fluoroquinolones, which inhibits the bacterial growth by inhibiting DNA gyrase, a type II topoisomerase and topoisomerase IV, enzymes, it is used against respiratory tract, abdominal tract, gastrointestinal and urinary tract infection; B) Nitrofurantoin, they react with flavoproteins and reduces to various multiple reactive intermediates that attack the ribosomal protein, DNA, pyruvate metabolism and other macromolecules within the cell, the drug has been used to treat the urinary tract infections
2.2 DRUG RESISTANCE AND MECHANISM OF RESISTANCE
Drug resistance is an ever increasing worldwide health threat that involves all major
microbial pathogens and antimicrobial drugs (Stuart and Bonnie, 2005). Antimicrobial can be
categorized according to their principal mechanism of action, which includes, 1) Interference
with cell wall synthesis (beta-lactams and glycopeptide agents), 2) Inhibition of protein
synthesis (macrolides and tetracyclines), 3) Interference with nucleic acid synthesis
(fluoroquinolones and rifampin), 4) Inhibition of a metabolic pathway (trimethoprim-
sulfamethoxazole), 5) Disruption of bacterial membrane structure (polymyxins and
daptomycin) (Tenover, 2006), as discussed above (2.1). The microbial resistance is the ability
of microbes to grow in the presence of antibiotics. The difference between non- resistant and
resistant bacteria is described in Figure 2.11, which shows drug resistant bacteria are not
controlled or killed my antibiotics, whereas in the case of non- resistant bacteria they die in the
presence of antibiotics. Antibiotic resistance has increased substantially in recent years and
considered as fast growing therapeutic problem (Guillemot 1999; Austin et al., 1999). The
development of antibiotic resistance can be natural or intrinsic and acquired which can be
transmitted within same or different species of bacteria. In inherent (natural) resistance is the
innate ability of bacteria to resist activity of a particular antibiotic through its inherent
structural or functional characteristics, due to which it can tolerate a particular drug or
antimicrobial class. It may be because of lack of transport system, inaccessibility of the drug
into the bacterial cell, extrusion of the drug by chromosomally encoded active exporters or
innate production of enzymes that inactivate the drug. Acquired resistance includes vertical