Microbiology is the study of microorganisms too small to be seen with the naked eye, including bacteria, viruses, protozoa, fungi, and algae. This document discusses microbiology and focuses on bacteria and urinary tract infections. It defines key terms related to pathogenicity and infection. It also outlines the structures and features of bacteria, how they are classified, and their role in both causing disease and benefiting humans. The document discusses the portals of entry for bacteria, including the respiratory tract, gastrointestinal tract, skin, and mucous membranes. Finally, it examines the causes, definitions, and pathogenesis of urinary tract infections.
4. 2012
Microbiology
It is the science of the microorganisms which
include unicellular organisms:
It consists of 5 groups of organisms:
Unicellular algae.
Bacteria
Viruses
Protozoa
fungi
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Cell is the basic unit of life..
• Based on the organization of their cellular structures all living cells
can be divided into two groups:
• Prokaryotic & Eukaryotic
• e.g. Animals, plants fungi protozoa’s and algae all possess
Eukaryotic cell types, Only Bacteria have Prokaryotic cell types.
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Structural Features of BacteriaFeatures Functions
All Bacteria Possess:
Nuclear Material
Cytoplasm
Ribosomes
Cytoplasmic Membrane
Cell Wall
The controlling center of the cell.
A viscous fluid containing the cellular contents.
Structures which manufacture proteins under direction of nuclear material
A selectively-permeable membrane surrounding the cytoplasm which
controls the flow of material into and out of the cell.
A freely permeable but rigid structure which gives the cell its shape.
Some Bacteria also Possess:
Capsule
Flagella
Fimbriae
Spores
A protective coating around the cell wall.
Long spiral thread proper the cell for movement.
Fine hairs which help the cell adhere to the surfaces.
A version of the bacterial cell which is highly resistant to adverse
conditions.
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The Bacterial Cell Wall
The bacterial Cell Wall provides Structural Integrity to the cell.
The Bacterial Cell wall differs from that of all other organisms by the presences of
Peptidoglycan, which is located immediately outside of the Cytoplasmic Membrane.
Peptidoglycan is responsible for the Rigidity of the Bacterial Cell wall and for the
Determination of Cell Shape.
It is freely permeable to Water and Small Solutes. It ‘ld considered relatively porous
and not considered to be a permeability barrier.
N.B. Intracellular parasites such as Mycoplasma (contain peptidoglycan,
not all cell walls have the same overall structures)
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Classification of Bacteria
Biological classification of bacteria is done
on basis of common characteristics such
as:
A: Morphology.
B: Gram Staining.
C: Oxygen Requirements.
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Classification according to the Shape
1. Rod-shaped (Bacillus)
2. Round (Coccus, e.g. Streptococcus)
3. Spiral (Spirillum)
4. An additional group, (Vibrios), appears as
incomplete spirals.
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Classification according to the Gram Stain
• Gram Positive Bacteria: Single layered Cell Wall
containing a thick peptidoglycan layer and
Teichoic acids.
• Gram Negative Bacteria: more complex Multi-
layered cell wall. Has two layer of phospholipid
and a thin Peptidoglycan layer located in the
Periplasm (the region between the outer and
inner Cytoplasmic membranes)
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Classification according to the Oxygen Need
Strict (Obligatory) Anaerobes:
Grow only were oxygen is absent.
Clostridium, strict anaerobes grow only were oxygen is absent.
Microaerephilic:
Survive with a little oxygen.
Require oxygen but grow best just below the surface of the agar where oxygen is reduced.
Facultative Anaerobes:
Can survive with or without oxygen.
Escherichia, Enterobacter, and Proteus grow best in oxygen but can grow in the absence of
oxygen by stealing oxygen from foods such as nitrates, sugars.
Strict (Obligatory) Aerobes:
Can’t survive without oxygen (areas rich in blood)
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Bacterial Nutrition
1.Carbon: Basic for all organic compounds.
Required in large quantities.
2. Water: Required for bacterial growth.
Some species survive without moisture in the form of spores.
3. Nitrogen: For protein synthesis.
4. Minerals: Phosphorous, K, Na, Sulpher, Fe, Mg & Ca.
5. Vitamins: For some bacteria. e.g. Gut bacteria
produce vitamins.
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Phases of Bacterial Growth
15
Picture of
the phases
Individ
ual
bacteria
are
Maturi
ng &
not yet
able to
Divide!
Individual
bacteria at their
maximum rate,
therefore number
increases during
this phase
Growth rate
slows due to
depletion of
nutrients,
this phase is
reached as
bacteria
begin to
exhaust the
resources
that are
available to
them.
Bacteria run out
of nutrients and
die
16. 2012
Factors Affecting Bacterial Growth
1. Temperature:
Minimum Temperature: (from 0 to 10 C)
Most bacteria are unable to grow at these temperature.
Optimum Temperature: (from 10 to 50 C)
Optimum temperature for growth of many pathogens
Maximum Temperature: (up to 80 C)
Most pathogens are killed at this temperature
“Temperature required to kill spores ( from 90 to 120 C)”
2. Oxygen:
3. PH Range: Growth of majority is limited to PH range of 2 (one above to one below their
optimum PH)
• Acidophile (PH less than 5.4)
Neutrophile (PH 5.8- 8.5)
Alkaliphile (PH 7.0 -11.5)
4. Moisture. 5. Light 6. Nutrients
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Organisms included in the study of
Microbiology
• 1. Bacteria
• 2. Protozoans
• 3. Algae
• 4. Parasites
• 5. Yeasts and Molds
– Fungi
• 6. Viruses
• Bacteriology
• Protozoology
• Phycology
• Parasitology
• Mycology
• Virology
Microorganisms - Microbes - Germs
18. 2012
Bacteria - what comes to mind?
• Diseases
• Infections
• Epidemics
• Food Spoilage
• Only 1% of all known bacteria cause human
diseases
• About 4% of all known bacteria cause plant diseases
• 95% of known bacteria are non-pathogens
19. 2012
Microbes Benefit Humans
• 1.Bacteria are primary decomposers - recycle
nutrients back into the environment (sewage
treatment plants)
• 2. Microbes produce various food products
– cheese, pickles, sauerkraut, green olives
– yogurt, soy sauce, vinegar, bread
– Beer, Wine, Alcohol
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Bacteria synthesize chemicals that our body
needs, but cannot synthesize
• Example: E. coli
– B vitamins - for metabolism
– Vitamin K - blood clotting
• Escherichia coli
– Dr. Escherich
– Colon (intestine)
22. Some Important Pathogens:
COCCI
Gram positive Cocci Gram negative Cocci
Staphylococcus S. Saprophyticus
Staph. epidermidis
Staphylococcus aureus
Streptococcus spp S. Viridans
Strep. Pyogene
Strep. Pneumonia
Enterococcus spp E. faecalis, E. faecium
Viridans-type streps
Neissena spp.
Branhamella spp.(Chest infection)
Moraxella catarrhalis
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PATHOGENICITY vs. VIRULENCE
PATHOGENICITY: the quality of producing disease or
the ability to produce pathologic changes or disease
VIRULENCE: a measure of pathogenicity; a measurement
of the degree of disease-producing ability of a microorganism
as indicated by the severity of the disease produced.
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PATHOGENICITY vs. VIRULENCE
(Definitons)
DOSAGE: the number of pathogenic microorganisms
entering the host
LD50 = the number of microorganisms required to cause
lethality (death) in 50% of the test host
TRUE PATHOGEN: any microorganism capable of
causing disease; an infecting agent
OPPORTUNISTIC PATHOGEN: a usually harmless
microorganism that becomes pathogenic under favorable
conditions causing an opportunistic infection
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INFECTION vs. DISEASE
INFECTION: the colonization and/or invasion and
multiplication of pathogenic microrganisms in the host
with or without the manifestation of disease
DISEASE: an abnormal condition of body function(s)
or structure that is considered to be harmful to the affected
individual (host); any deviation from or interruption of the
normal structure or function of any part, organ, or system
of the body
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Bacterial Pathogenicity
Infection Results from:
Invasion of the body by pathogenic bacteria.
Contamination of tissues by normally harmless bacteria which
outside their normal habitat become virulent.
Predisposing Factors to Infection:
Immunosupressed Patients.
Extremes of Age.
Malnutrition.
Poor Personal Hygiene.
Diabetes.
Hospital Admission.
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1. Mucus Membranes
• A. Respiratory Tract
– microbes inhaled into
mouth or nose in
droplets of moisture or
dust particles
– Easiest and most
frequently traveled
portal of entry
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Common Diseases contracted via
the Respiratory Tract
• Common cold
• Flu
• Tuberculosis
• Whooping cough
• Pneumonia
• Measles
• Strep Throat
• Diphtheria
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Mucus Membranes
• B. Gastrointestinal Tract
– microbes gain entrance thru
contaminated food & water or
fingers & hands
– most microbes that enter the
G.I. Tract are destroyed by
HCL & enzymes of stomach or
bile & enzymes of small
intestine
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Fecal - Oral Diseases
• These pathogens enter the G.I. Tract at one
end and exit at the other end.
• Spread by contaminated hands & fingers or
contaminated food & water
• Poor personal hygiene.
36. 2012
Mucus Membranes of the Genitourinary System - STD’s
Gonorrhea
Neisseria gonorrhoeae
Syphilis
Treponema pallidum
Chlamydia
Chlamydia trachomatis
HIV
Herpes Simplex II
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Introduction
* UTIs are common, especially among women
* UTIs in men are less common and primarily
occur after 50 years of age
* UTIs infection usually occur by ascending route (urethra to bladder)
* UTIs infection is less common by haematogenous spread (kidney)
* UTIs occur in two general settings: community-acquired and hospital
(nosocomially) acquired
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Definitions
Urethritis : Infection of anterior urethral tract
dysuria, urgency
and frequency of micturition
- Dysuria (burning pain on passing urine)
- Urgency (the urgent need to pas urine)
- Frequency of micturition
* Cystitis : Infection of urinary bladder
dysuria, frequency, pyuria and
haematuria
* Bacteriuria: Presence of bacteria in urine
A count of 10 organisms/ml or more in urine
* Pyuria : Presence of pus in urine
(more than 10 cells/HPF)
• Pyelonephritis: Infection of kidney (lion pain, pyuria,
rigors
,fever
40. 2012
Etiology Of Urinary Tract Infections
* Causative organisms:
Escherichia coli
Klebsiella, proteus and pseudomonas
1- Bacterial S. aureus, S. epidermidis and S. saprophyticus
Enterococci (Strept. faecalis)
Mycobacterium tuberculosis
Chlamydia trachomatis, Mycoplasma
2- Viral Rubella, Mumps and HIV
3- Fungal Candida, Histoplasma capsulatum
4- Protozoal T. vaginalis, S. haematobium
41. 2012
Notes on pathogens
* Escherichia coli : the commonest urinary pathogen
causing 60-90 % of urinary infections
* Pseudomonas, Proteus, Klebsiella and S. aureus
are associated with hospital acquired infections because their resistance to
antibiotics favor their selection in hospital patients
(catheterization, gynaecological surgery)
* Proteus infections are associated with renal stones
Proteus produce a potent urease which act on ammonia, rendering the urine
alkaline
* S. saprohyticus infections are found in
sexually active young women
42. 2012
Notes on pathogens
* Candida urinary infection is usually found in diabetic patients and
immunosuppression
* Infection of the anterior urinary tract (urethritis) is mainly caused
by N. gonorrhoae, staphylococci, streptococci and chlamydiae
* M. tuberculosis is carried in blood to kidney from another site of
infection
(e.g. respiratory T.B.)
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Mechanical And Functional Factors Predispose to UTI
* Disruption of urine flow or complete emptying of bladder
- Pregnancy - Renal stones -Tumor
- Prostate hypertrophy - Strictures = narowing of ureter
* Loss of neurologic control of bladder and sphincters
Paraplegia, and multiple sclerosis
Paraplegia
multiple sclerosis
* Vesicouretral reflux
(reflux of urine from bladder up the ureter)
Anatomic abnormalities in children
* Catheterization facilitate bacterial access to bladder
- During insertion
- In situ, bacteria access to bladder
44. 2012
Virulence Factors of Causative Organisms
- Fimbriae enable adherence to urethral epithelium
- Capsular polysaccharide inhibite phagocytosis
- Haemolysin production by E. coli
-Membrane damaging toxin
- Production of urease enzyme (proteus spp.)
45. 2012
Healthy Urinary Tract
Bacterial colonization in urinary tract is
prevented by:
- pH of urine (acidic)
- Chemical content of urine
- Flushing mechanisms
46. 2012
Clinical Features
Acute lower UTIs (Urithritis and cystitis):
Rapid onset of:
- Dysuria (burning pain on passing urine)
- Urgency (the urgent need to pas urine)
- Frequency of micturition
Upper UTIs (Pyelonephritis):
- Fever
- Chills
- Dysuria
- Urgency
- Frequency of micturition
47. 2012
Chronic prostatitis
The most common pathogens in prostatitis
Etiologically recognized pathogens
Escherichia coli
Staphylococci
Klebsiella spp.
Chlamydia trachomatis
Proteus mirabilis
Ureaplasma urealyticum
Other pathogens of the Enterobacteriaceae family Mycoplasma
Enterococcus faecalis
Pseudomonas aeruginosa
48. 2012
Mucus Membranes
• D. Conjunctiva –
– mucus membranes that cover
the eyeball and lines the eyelid
• Trachoma
– Chlamydia trachomatis
49. 2012
2nd Portal of Entry: Skin
• Skin - the largest organ of the body. When
unbroken is an effective barrier for most
microorganisms.
• Some microbes can gain entrance thru
openings in the skin: hair follicles and sweat
glands
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3rd Portal of Entry: Parentarel
• Microorganisms are deposited into the tissues
below the skin or mucus membranes
• Punctures
• injections
• bites
• scratches
• surgery
• splitting of skin due to swelling or dryness
51. 2012
Preferred Portal of Entry
• Just because a pathogen enters your body it
does not mean it’s going to cause disease.
• pathogens - preferred portal of entry
52. 2012
Preferred Portal of Entry
• Streptococcus pneumoniae
– if inhaled can cause pneumonia
– if enters the G.I. Tract, no disease
• Salmonella typhi
– if enters the G.I. Tract can cause Typhoid Fever
– if on skin, no disease
53. 2012
How do Bacterial Pathogens penetrate Host
Defenses?
1. Adherence -
almost all pathogens have
a means to attach to host
tissue
Binding Sites
adhesins
ligands
54. 2012
Adhesins and ligands are usually
on Fimbriae
• Neisseria gonorrhoeae
• ETEC (Entertoxigenic E.
coli)
• Bordetello pertussis
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A. Leukocidins
• Attack certain types of WBC’s
• 1. Kills WBC’s which prevents phagocytosis
• 2. Releases & ruptures lysosomes
– lysosomes - contain powerful hydrolytic enzymes which
then cause more tissue damage
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C. Coagulase - cause blood to coagulate
• Blood clots protect bacteria from phagocytosis
from WBC’s and other host defenses
• Staphylococci - are often coagulase positive
– boils
– abscesses
63. 2012
D. Kinases - enzymes that dissolve blood
clots
• 1. Streptokinase - Streptococci
• 2. Staphylokinase - Staphylococci
• Helps to spread bacteria - Bacteremia
• Streptokinase - used to dissolve blood clots in the Heart
(Heart Attacks due to obstructed coronary blood vessels)
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E. Hyaluronidase
• Breaks down Hyaluronic acid (found in connective
tissues)
• “Spreading Factor”
• mixed with a drug to help spread the drug
thru a body tissue
65. 2012
F. Collagenase
• Breaks down collagen (found in many connective
tissues)
• Clostridium perfringens - Gas Gangrene
– uses this to spread thru muscle tissue
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G. Necrotizing Factor
- causes death (necrosis) to tissue cells
“Flesh Eating Bacteria”
Necrotizing fasciitis
67. 2012
4. Toxins
• Poisonous substances produced by
microorganisms
• toxins - primary factor - pathogenicity
• 220 known bacterial toxins
– 40% cause disease by damaging the Eukaryotic cell
membrane
• Toxemia
– Toxins in the bloodstream
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2 Types of Toxins
• 1. Exotoxins
– secreted outside the bacterial cell
• 2. Endotoxins
– part of the outer cell wall of Gram (-) bacteria
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ENDOTOXINS
1.IInntteeggrraall ppaarrtt ooff cceellll wwaallll
2.Endotoxin is LLPPSS;
lipid A is toxic
3.Heat stable
4.Antigenic; questionable
immunogenicity
5.Toxoids not be produced
6.Many effects on host
7.Produced oonnllyy bbyy ggrraamm--
nneeggaattiivvee organisms
EXOTOXINS
1.RReelleeaasseedd ffrroomm tthhee cceellll
before or after lysis
2.PPrrootteeiinn
3.Heat labile
4.Antigenic and iimmmmuunnooggeenniicc
5.TTooxxooiiddss can be produced
6.Specific in effect on host
7.Produced by gram-positive
& gram-negative organisms
70. 2012
Summary of How Bacterial Pathogens
Penetrate Host Defenses
• 1. Adherence
• 2. Capsule
• 3. Enzymes
– A. leukocidins
– B. Hemolysins
– C. Coagulase
– D. Kinases
– E. Hyaluronidase
– F. Collagenase
– G. Necrotizing Factor
4. Toxins
72. 2012
Definitions of Antibiotics
• OLD: An antibiotic is a chemical substance
produced by various species of microorganisms that
is capable in small concentrations of inhibiting the
growth of other microorganisms
• NEW: An antibiotic is a product produced by a
microorganism or a similar substance produced
wholly or partially by chemical synthesis, which in low
concentrations, inhibits the growth of other
microorganisms
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History
Selman Waksman
– Soil Streptomyces make antibiotics
– comes up with definition of antibiotic
ORIGIN: Penicillin development
DRUG: Streptomycin (1943)
NOBEL: 1952
(cont’d)
78. 2012
Factors that effect Antimicrobial
Activity
• 1. Temp
• 2. Time
• 3. Concentration of Antimicrobial agent
• 4. Type of Microbe
• 5. Activity of Microbe
• 6. Presence of organic matter
80. 2012
The Ideal Drug*
1. Selective toxicity: against target pathogen but not against host
– LD50 (high) vs. MIC and/or MBC (low)
1. Bactericidal vs. bacteriostatic
2. Favorable pharmacokinetics: reach target site in body with
effective concentration
3. Spectrum of activity: broad vs. narrow
4. Lack of “side effects”
– Therapeutic index: effective to toxic dose ratio
1. Little resistance development
* There is no perfect drug.
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Antibacterial spectrum—Range of activity
of an antimicrobial against bacteria. A
broad-spectrum antibacterial drug can
inhibit a wide variety of gram-positive and
gram-negative bacteria, whereas a
narrow-spectrum drug is active only
against a limited variety of bacteria.
Bacteriostatic activity—-The level of
antimicro-bial activity that inhibits the
growth of an organism. This is determined
in vitro by testing a standardized
concentration of organisms against a
series of antimicrobial dilutions. The
lowest concentration that inhibits the
growth of the organism is referred to as
the minimum inhibitory concentration
(MIC).
Bactericidal activity—The level of
antimicrobial activity that kills the test
organism. This is determined in vitro by
exposing a standardized concentration of
organisms to a series of antimicrobial
dilutions. The lowest concentration that
kills 99.9% of the population is referred to
as the minimum bactericidal
concentration (MBC).
Antibiotic combinations—Combinations of
antibiotics that may be used (1) to broaden
the antibacterial spectrum for empiric
therapy or the treatment of polymicrobial
infections, (2) to prevent the emergence of
resistant organisms during therapy, and (3)
to achieve a synergistic killing effect.
Antibiotic synergism—Combinations of
two antibiotics that have enhanced
bactericidal activity when tested together
compared with the activity of each
antibiotic.
Antibiotic antagonism—Combination of
antibiotics in which the activity of one
antibiotic interferes With the activity of the
other (e.g., the sum of the activity is less
than the activity of the individual drugs).
Beta-lactamase—An enzyme that
hydrolyzes the beta-lactam ring in the
beta-lactam class of antibiotics, thus
inactivating the antibiotic. The enzymes
specific for penicillins and cephalosporins
aret he penicillinases and
cephalosporinases, respectively.
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Modes of Antimicrobial Action
83
Inhibition of Cell Wall
Synthesis:
Penicillins,
Cephalosporins,
Bacitracin, Vancomycin
Inhibition of Protein
Synthesis:
Chloramphenicol,
Neomycin, Tetracycline,
Streptomycin
Injury to Plasma
membrane:
Polymyxin B
Inhibition of synthesis of
essential metabolites:
Sulfanilamide,
Trimethoprime
Inhibition of
Nucleic acid
replication &
transcription:
Quinolones,
Rifampin
84. 2012
Mechanism of action of antibiotics
Inhibition of cell wall
synthesis Inhibit the construction of the bacterial cell wall by interfering
with the transpeptidase enzyme responsible for the formation of
peptide cross linkage preventing the cross linkage, finally the cell
bursts as a result of the growing internal pressure.
Penicillin
Cephalosporins
Bacitracin zinc
Inhibition of protein
synthesis
1.Inside a bacterial cell, proteins are manufactured at certain
structures known as Ribosomes
2. Erythromycin, lincomycin, and Chloramphenicol bind to the so
called 50s component of the ribosome and prevent the
movement of mRNA
3. Aminoglycosides and tetracycline bind to the so called 30s
component of the ribosome and interfere with protein synthesis
in other ways.
4. Protein synthesis comes to a halt and the bacterial cell
becomes unable to function and may die or susceptible to
destruction
Tetracycline
Neomycin
Macrolides
Chloramphenicol
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Mechanism of action of antibiotic
Inhibition of DNA replication
Mode of action depends upon blocking
bacterial DNA replication by binding itself
to an enzyme called DNA gyrase, causing
double-stranded breaks in the bacterial
chromosome.
Quinolones
Inhibition of folic acid metabolism Folic acid (one of the B vits) is responsible
for the biosynthesis of nucleic acids (DNA
building blocks)Sulphonamide
Injury to Plasma membrane
Polymyxin B
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Penicillin
Mode of action: Interfere with cell wall synthesis
Broad spectrum penicillin:
i. Ampicillin
ii. Amoxyclillin
iii. Amoxyclillin+ Clavulanic acid
iv. Amoxycillin + Cloxacillin
v. Amoxycillin + Flucoxacillin
vi. Ampicillin + Sulbatam
Narrow spectrum Penicillin:
i. Penicillin G
ii. Cloxacillin
iii. Fucoxacillin
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Cephalosporins
Mode of action: Interfere with cell wall synthesis.
1st
generation
i. Cephazone
ii. Cephalexine
iii. Cephardine
iv. cephadroxil
2nd
generation
i. Cefuroxime
ii. Cephamandole
3rd
generation
i. Cefotaxime
ii. Ceftazidime
iii. Ceftraiaxone
iv. Cefoperazone
4th
generation
i. Cefepime
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Quinolones
Mode of Action: Blocking Bacterial DNA replication by inhibiting
DNA gyrase enzyme
i. Ofloxacin
ii. Ciprofloxacin
iii. Levofloxacin
iv. Naledixic acid
v. Pefloexacin
vi. Nor floxacin
vii.Moxifloxacin
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Aminoglycosides
• Aminoglycosides that are derived from bacteria of the Streptomyces
genus
• Mode of Action: Inhibition of protein synthesis
1. Amikacin
2. Arbekacin
3. Gentamicin
4. Kanamycin
5. Neomycin
6. Netilmicin
7. Paromomycin
8. Rhodostreptomycin
9. Streptomycin Tobramycin
10. Apramycin
90
92. 2012
Origin of Drug Resistance
• Genetic
– spontaneous mutation of old genes
• Vertical evolution
– Acquisition of new genes
• Horizontal evolution
• Chromosomal Resistance
• Extrachromosomal Resistance
(cont’d)
93. 2012
Implications
of Resistance
• Household agents
– they inhibit bacterial growth
– purpose is to prevent transmission of disease-
causing microbes to noninfected persons.
– can select for resistant strains
• NO evidence that they are useful in a healthy
household
94. 2012
Implications of Resistance
• Triclosan studies
– effect diluted by water
– one gene mutation for resistance
– contact time exceeds normal hand wash time (5
seconds)
• Allergies
– link between too much hygiene and increased allergy
frequency
What is the role of antibiotic in nature:
Germ Warfare- the production of compounds that discourage microbial competitors. Problem with this explanation is that antibiotic production by microbes growing in nature is so low that levels of antibiotics are undetectable.
May be signaling molecules
NO EVIDENCE FOR EITHER ROLE
Paul Ehrlich- derived from finding that dyes used in histochemistry became bound to cell-specific receptors. He asked” Why can’t such dyes be toxic for specific organisms?”
1910 looking for something to target Treponema pallidum. Looked at arsenic compounds and on the 606th one tested. Salvarsan- combo of salvation and arsenic. First documented case of a chemicla that could selectively kill pathogens w/o permanently harming the human host.
In 1934, found that protosil cured a fatal streptococcal infection in mice - did not work in test tube.
prontosil sulfanilamide
didn’t work in tt, but working in animal. Turns out that prontosil was split by a enzymes in animals blood into the first of the “Sulfa drugs”
The cure rates for some diseases were rising and these findings gave impetus to the efforts to purify penicillin.
Alexander Fleming
penicillin developed in US in 1941 - spores from mold on coats of scientists
Selman Waksman
streptomycin - bacteria produced antibiotics too. Many began screening soils looking for antibiotics.
Selective toxicity - greater harm to microbes than host, done by interfering with essential biological processes common in bacteria but not human cells.
LD50 vs. MIC - Therapeutic index (the lowest dose toxic to the patient divided by the dose typically used for therapy). High TI are less toxic to the patient.
Bactericidal vs. bacteriostatic
Static rely on normal host defences to kill or eliminate the patogen after its growth has been inhibited. (UTIs) CIDAL given when host defenses cannot be relied on to remove or destroy pathogen.
Favorable pharmacokinetics - drug interxns, how drug is distributed, metabolized and excreted in body (unstabel in acid, can it cross the Blood-brain barrier, etc)
Spectrum of activity
broad spectrum - wide
Narrow spectrum - narrow range (pathogen must be ID’d)
Lack of “side effects” allergic, toxic side effects, suppress normal flora
Little resistance development
Spontaneous evolution occurs at low rate (~1 in 10 million cells)
Grow up 10 to the 9 or tenth cells, there is a good chance one cell is resistant to Streptomycin due to mutation, plate the load, isolate the resistant.
Streptomycin: binds to 30S subunit of ribsome
causes distortion and misreading
Single target, easy to get spontaneuos mutation. Multiple targets are harder b/c several different mutations are required to prevent binding of the drug.
Plasmids
Transposons
Integrons
Thus if organism has two different plasmids, an antibiotic resistant gene can move from one to another. In this way, a gene could move from a narrow range host plasmid to a wide range host plasmid. Wide range host plasmids, in contrast to narrow range host plasmids, can replicate even if they are transferred to unrelated bacteria.
High therapeutic index
some block NAM elongation-Vancomycin
precursor transport blockage - Bacitracin
β-lactam drugs
beta lactam ring has structural similarity between normal substrate (for enzymes known as penicillin binding proteins (PBPs) By mimicking the substrate the beta lactam drugs are bound by PBPs thus competitively inhibiting their enzymatic activity. This causes a disruption in CW synthesis. B/c CW are only synthesized in actively multiplying cells, these are only effective against growing bacteria.
Some make beta lactamse, an enzyme that breaks down the ring structure and thus inactivates penicillins
Tend to be bactericidal and broad spectrum
Are actively transported onto the bacterial cell (this is one reason for selective toxicity - don’t work against animal cells) by a mechanism that involves ox phos. Therefore, they have little or no activity against strict anaerobes or those that metabolize only fermentatively (like streptococci)
Gentamicin
Tobramycin
Amikacin
Streptomycin - hardly used anymore b/c high-level and stable resistant mutants are frequently selected for during therapy
Kanamycin
Spectinomycin
Neomycin - used to reduce the facultative flora of the large intestine befroe certain types of intestinal surgury. It is poorly absorbed therefore is active in the bowel.
use along with other drugs for TB
Tend to be very toxic.
Have a cationic detergent effect, bind to cell membranes of Gm neg and alter permeability. Toxicity due to the effect that it has on cell membranes as well.
USed topically and have the advantage that resistance to them rarely develops
nephrotoxic and neurotoxic
broad spectrum, cidal?
Very few that do this.
Most useful are folate inhibitors sulfonamide and trimethoprim. Inhibit various steps in the pathway for folic acid that ultimately blocks the synthesis of a coenzyme required for nucleotide synthesis. Animal cells lack the enzymes in the folic acid synthesis portion of the pathway which is why folic acid is a dietary requirement.
Difference in the activity of the various sulfonamides reflect their ability to compete with PABA for the enzyme. High urine levels are achieved and is excreted in urine in active form therefore good for UTIs.