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7-8_Chemotherapy of Bacterial Infections. Antibiotics

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Chemotherapy of Bacterial Infections ~~~~~~~~ Antibiotics

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Слайд 1

Слайд 2 Chemotherapy of Bacterial Infections ~~~~~~~~ Antibiotics

Chemotherapy of Bacterial Infections ~~~~~~~~ Antibiotics

Слайд 3Definitions 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


Definitions of AntibioticsOLD: An antibiotic is a chemical substance produced by various species of microorganisms that is

Слайд 4Impact of Modern Healthcare on Life Expectancy

Impact of Modern Healthcare on Life Expectancy

Слайд 5History
Paul Ehrlich
“Magic Bullet”
Chemicals with selective toxicity

ORIGIN: Selective Stains
DRUG: Arsphenamine (1910)
“606” Salvarsan

NOBEL: 1908

HistoryPaul Ehrlich “Magic Bullet” Chemicals with selective toxicityORIGIN: Selective StainsDRUG: Arsphenamine (1910) “606” SalvarsanNOBEL: 1908

Слайд 6History
(cont’d)
Gerhard Domagk
Drugs are changed in the body

ORIGIN: Prontosil
(Only active in

vivo)
DRUG: Sulfanilamide (1935)

NOBEL: 1939

History(cont’d)Gerhard Domagk Drugs are changed in the bodyORIGIN: Prontosil (Only active in vivo)DRUG: Sulfanilamide (1935)NOBEL: 1939

Слайд 7History
Alexander Fleming
Microbes make antibiotics

ORIGIN: moldy culture plate
DRUG: Penicillin (1928)

NOBEL: 1945
(cont’d)

HistoryAlexander Fleming Microbes make antibioticsORIGIN: moldy culture plateDRUG: Penicillin (1928)NOBEL: 1945(cont’d)

Слайд 8History
(cont’d)
Selman Waksman
Soil Streptomyces make antibiotics
comes up with definition

of antibiotic

ORIGIN: Penicillin development
DRUG: Streptomycin (1943)

NOBEL: 1952

History(cont’d)Selman Waksman Soil Streptomyces make antibiotics comes up with definition of antibioticORIGIN: Penicillin developmentDRUG: Streptomycin (1943)NOBEL: 1952

Слайд 9The Ideal Drug*
Selective toxicity: against target pathogen but not

against host
LD50 (high) vs. MIC and/or MBC (low)
Bactericidal vs.

bacteriostatic
Favorable pharmacokinetics: reach target site in body with effective concentration
Spectrum of activity: broad vs. narrow
Lack of “side effects”
Therapeutic index: effective to toxic dose ratio
Little resistance development

* There is no perfect drug.

The Ideal Drug*Selective toxicity: against target pathogen but not against host LD50 (high) vs. MIC and/or

Слайд 12Susceptibility Tests
1. Broth dilution - MIC test
2. Agar dilution - MIC test

Susceptibility Tests1. Broth dilution - MIC test2. Agar dilution - MIC test

Слайд 13Minimal Inhibitory Concentration (MIC)
vs.
Minimal Bactericidal Concentration (MBC)

Minimal Inhibitory Concentration (MIC)vs.Minimal Bactericidal Concentration (MBC)

Слайд 14Susceptibility Tests
Agar diffusion
 Kirby-Bauer Disk Diffusion Test

(cont’d)

Susceptibility TestsAgar diffusion  Kirby-Bauer Disk Diffusion Test(cont’d)

Слайд 15Susceptibility Tests “Kirby-Bauer Disk-plate test”
Diffusion depends upon:
Concentration
Molecular weight
Water solubility
pH and ionization
Binding

to agar
(cont’d)

Susceptibility Tests “Kirby-Bauer Disk-plate test”Diffusion depends upon:ConcentrationMolecular weightWater solubilitypH and ionizationBinding to agar (cont’d)

Слайд 16Susceptibility Tests “Kirby-Bauer Disk-plate test”
Zones of Inhibition (~ antimicrobial activity) depend

upon:
pH of environment
Media components
Agar depth, nutrients
Stability of drug
Size of inoculum
Length

of incubation
Metabolic activity of organisms

(cont’d)

Susceptibility Tests “Kirby-Bauer Disk-plate test”Zones of Inhibition (~ antimicrobial activity) depend upon:pH of environmentMedia componentsAgar depth, nutrientsStability

Слайд 17Antibiotic Mechanisms of Action
Transcription
Translation
Translation
Alteration of Cell Membrane Polymyxins Bacitracin Neomycin

Antibiotic Mechanisms of ActionTranscriptionTranslationTranslationAlteration of Cell Membrane Polymyxins Bacitracin Neomycin

Слайд 18Mechanism of Action
ANTIMETABOLITE ACTION
Sulfonamides
an analog of PABA, works by competitive

inhibition

Trimethoprim-sulfamethoxazole
a synergistic combination; useful against

UTIs
Mechanism of ActionANTIMETABOLITE ACTIONSulfonamides an analog of PABA, works by competitive inhibitionTrimethoprim-sulfamethoxazole a synergistic

Слайд 19Mechanism of Action ANTIMETABOLITE ACTION
(cont’d)
tetrahydrofolic acid

Mechanism of Action ANTIMETABOLITE ACTION(cont’d)tetrahydrofolic acid

Слайд 20Mechanism of Action
2. ALTERATION OF CELL MEMBRANES
Polymyxins and colistin
destroys membranes
active against

gram negative bacilli
serious side effects
used mostly for skin &

eye infections

(cont’d)

Mechanism of Action2. ALTERATION OF CELL MEMBRANESPolymyxins and colistindestroys membranesactive against gram negative bacilliserious side effects used mostly

Слайд 21Mechanism of Action ALTERATION OF CELL MEMBRANES
(cont’d)

Mechanism of Action ALTERATION OF CELL MEMBRANES (cont’d)

Слайд 22Mechanism of Action
INHIBITION OF PROTEIN SYNTHESIS:
Steps in synthesis:
Initiation
Elongation
Translocation
Termination
(cont’d)
Prokaryotes and eukaryotes

(80S) have a different structure to ribosomes so can use

antibiotics for selective toxicity against ribosomes of prokaryotes (70S)
Mechanism of ActionINHIBITION OF PROTEIN SYNTHESIS: Steps in synthesis:InitiationElongationTranslocationTermination(cont’d)Prokaryotes and eukaryotes (80S) have a different structure to ribosomes

Слайд 23Mechanism of Action INHIBITION OF PROTEIN SYNTHESIS
(cont’d)
Aminoglycosides
bind to bacterial ribosome

on 30S subunit; and blocks formation of initiation complex. Both

actions lead to mis-incorporation of amino acids
Examples:
Gentamicin Tobramycin
Amikacin Streptomycin
Kanamycin Spectinomycin
Neomycin
Mechanism of Action INHIBITION OF PROTEIN SYNTHESIS (cont’d)Aminoglycosides bind to bacterial ribosome on 30S subunit; and blocks

Слайд 24Mechanism of Action INHIBITION OF PROTEIN SYNTHESIS
(cont’d)
Aminoglycosides (cont’d)
broad spectrum
Gram negative

rods
P. aeruginosa
Drug-resistant gram negative rods
Plague, Tularemia, Gonorrhea
Pre-op (bowel)
External (skin)
toxic

at some level to eighth cranial nerve

Mechanism of Action INHIBITION OF PROTEIN SYNTHESIS (cont’d)Aminoglycosides (cont’d) broad spectrumGram negative rodsP. aeruginosaDrug-resistant gram negative rodsPlague,

Слайд 25Mechanism of Action INHIBITION OF PROTEIN SYNTHESIS
(cont’d)
Macrolides: chloramphenicol & erythromycin
bind

to 50S subunit and blocks the translocation step
Mycoplasma
Legionella
S. pyogenes


Chloramphenicol:

broad spectrum

Erythromycin:

Anaerobes
Typhoid
Meningitis

Mechanism of Action INHIBITION OF PROTEIN SYNTHESIS (cont’d)Macrolides: chloramphenicol & erythromycin bind to 50S subunit and blocks

Слайд 26Mechanism of Action INHIBITION OF PROTEIN SYNTHESIS
(cont’d)
Clindamycin
binds to 50S subunit

and interferes with binding of the amino acid – acyl-tRNA

complex and so inhibits peptidyl transferase
works best against
Staphylococcus
Bacteroides & anaerobic gram neg rods
Penicillin allergic people
Mechanism of Action INHIBITION OF PROTEIN SYNTHESIS (cont’d)Clindamycin binds to 50S subunit and interferes with binding of

Слайд 27Tetracyclines
bind to 30S subunit and interferes with the attachment

of the tRNA carrying amino acids to the ribosome
effective

against:
Chlamydia
Rickettsia
Mycoplasma
Brucella

Mechanism of Action INHIBITION OF PROTEIN SYNTHESIS

(cont’d)

Tetracyclines bind to 30S subunit and interferes with the attachment of the tRNA carrying amino acids to

Слайд 28Mechanism of Action
4. INHIBITION OF DNA/RNA SYNTHESIS
Rifampin
binds to RNA polymerase
active against

gram positive cocci
bactericidal for Mycobacterium
used for treatment and prevention of

meningococcus


(cont’d)

Mechanism of Action4. INHIBITION OF DNA/RNA SYNTHESISRifampinbinds to RNA polymeraseactive against gram positive coccibactericidal for Mycobacteriumused for treatment

Слайд 29Mechanism of Action INHIBITION OF DNA/RNA SYNTHESIS
Metronidazole
breaks down into

intermediate that causes breakage of DNA
active against:
protozoan infections
anaerobic gram

negative infections


(cont’d)

Quinolones and fluoroquinolones
effect DNA gyrase
broad spectrum

Mechanism of Action INHIBITION OF DNA/RNA SYNTHESISMetronidazole breaks down into intermediate that causes breakage of DNA

Слайд 30(cont’d)
Mechanism of Action INHIBITION OF DNA/RNA SYNTHESIS

(cont’d)Mechanism of Action INHIBITION OF DNA/RNA SYNTHESIS

Слайд 31Mechanism of Action
CELL WALL SYNTHESIS INHIBITORS
Steps in synthesis:
NAM-peptide made in

cytoplasm
attached to bactoprenol in cell membrane
NAG is added
whole piece is

added to growing cell wall
crosslinks added

the β-Lactams
the non β-Lactams

(cont’d)

Mechanism of ActionCELL WALL SYNTHESIS INHIBITORS Steps in synthesis:NAM-peptide made in cytoplasmattached to bactoprenol in cell membraneNAG is

Слайд 33Mechanism of Action
CELL WALL SYNTHESIS INHIBITORS
β-Lactam Antibiotics
Penicillins
Cephalosporins
Carbapenems
Monobactams
(cont’d)

Mechanism of ActionCELL WALL SYNTHESIS INHIBITORS β-Lactam AntibioticsPenicillinsCephalosporins CarbapenemsMonobactams(cont’d)

Слайд 34Mechanism of Action CELL WALL SYNTHESIS INHIBITORS
β-Lactam ring structure
(cont’d)

Mechanism of Action CELL WALL SYNTHESIS INHIBITORS β-Lactam ring structure(cont’d)

Слайд 36Mechanism of Action CELL WALL SYNTHESIS INHIBITORS
Action of β-Lactam antibiotics
(cont’d)
Bactericidal; growing

cells only
Drug links covalently to regulatory enzymes called PBPs (penicillin-binding

proteins)
Blocks cross-linkage of peptidoglycan
Mechanism of Action CELL WALL SYNTHESIS INHIBITORS Action of β-Lactam antibiotics(cont’d)Bactericidal; growing cells onlyDrug links covalently to

Слайд 37Mechanism of Action CELL WALL SYNTHESIS INHIBITORS
Action of β-Lactam antibiotics

(cont’d)
For E.

coli
> MIC
wall damage
autolysins
spheroplasting
cell lysis
< MIC
no septa
filaments

Mechanism of Action CELL WALL SYNTHESIS INHIBITORS Action of β-Lactam antibiotics(cont’d)For E. coli> MICwall damageautolysinsspheroplastingcell lysis< MICno

Слайд 39Resistance to β-Lactams – Gram pos.
Mechanism of Action CELL WALL SYNTHESIS

INHIBITORS
(cont’d)

Resistance to β-Lactams – Gram pos.Mechanism of Action CELL WALL SYNTHESIS INHIBITORS (cont’d)

Слайд 40Resistance to β-Lactams – Gram neg.

Mechanism of Action CELL WALL SYNTHESIS

INHIBITORS
(cont’d)

Resistance to β-Lactams – Gram neg.Mechanism of Action CELL WALL SYNTHESIS INHIBITORS (cont’d)

Слайд 41Non - β-Lactams

Mechanism of Action CELL WALL SYNTHESIS INHIBITORS
(cont’d)
Vancomycin
active against

gram positive cocci, but not gram negative because too large

to pass through outer membrane
interferes with PG elongation

Cycloserine, ethionamide and isoniazid
inhibits enzymes that catalyze cell wall synthesis
for Mycobacterial infections

Non - β-Lactams Mechanism of Action CELL WALL SYNTHESIS INHIBITORS (cont’d) Vancomycinactive against gram positive cocci, but not

Слайд 42Clinical Uses

Clinical Uses

Слайд 43Clinical Uses
(cont’d)

Clinical Uses (cont’d)

Слайд 44Resistance Physiological Mechanisms
1. Lack of entry – tet, fosfomycin
2. Greater

exit
efflux pumps
tet (R factors)
3. Enzymatic inactivation
bla

(penase) – hydrolysis
CAT – chloramphenicol acetyl transferase
Aminogylcosides & transferases
Resistance Physiological Mechanisms1. Lack of entry – tet, fosfomycin2. Greater exit efflux pumps tet (R factors)3.

Слайд 45Resistance Physiological Mechanisms
4. Altered target
RIF – altered RNA polymerase

(mutants)
NAL – altered DNA gyrase
STR – altered ribosomal

proteins
ERY – methylation of 23S rRNA
5. Synthesis of resistant pathway
TMPr plasmid has gene for DHF reductase; insensitive to TMP

(cont’d)

Resistance Physiological Mechanisms4. Altered target RIF – altered RNA polymerase (mutants) NAL – altered DNA gyrase

Слайд 46Origin of Drug Resistance
Non-genetic
metabolic inactivity
Mycobacteria
non-genetic loss of target
penicillin

– non-growing cells, L-forms
intrinsic resistance
some species naturally insensitive


Origin of Drug ResistanceNon-genetic metabolic inactivityMycobacteria non-genetic loss of targetpenicillin – non-growing cells, L-forms intrinsic resistancesome species

Слайд 47Origin of Drug Resistance
Genetic
spontaneous mutation of old genes
Vertical

evolution
Acquisition of new genes
Horizontal evolution

Chromosomal Resistance
Extrachromosomal Resistance
Plasmids, Transposons, Integrons

(cont’d)

Origin of Drug Resistance Genetic spontaneous mutation of old genesVertical evolutionAcquisition of new genesHorizontal evolutionChromosomal ResistanceExtrachromosomal ResistancePlasmids,

Слайд 48Plasmids
independent replicons
circular DNA
dispensable
several genes
drug resistance
metabolic enzymes

virulence factors
host range
restricted or broad

Plasmidsindependent replicons circular DNAdispensableseveral genes drug resistance metabolic enzymes virulence factorshost range restricted or broad

Слайд 49Plasmids
size
small, non-conjugal
large, conjugal

cells:
CONJUGATION (cell to cell contact)
due to plasmid tra genes

(for pili, etc)
NON-CONJUGAL
transduction
mobilization by conjugation plasmids

(cont’d)

Plasmidssize small, non-conjugal large, conjugal

Слайд 50Implications 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

Implications of ResistanceHousehold agents they inhibit bacterial growth purpose is to prevent transmission of disease-causing microbes to

Слайд 51Implications of Resistance
Triclosan studies
effect diluted by water
one gene

mutation for resistance
contact time exceeds normal handwash time (5

seconds)
Allergies
link between too much hygiene and increased allergy frequency
http://www.healthsci.tufts.edu/apua/ROAR/roarhome.htm
Implications of ResistanceTriclosan studies effect diluted by water one gene mutation for resistance contact time exceeds normal

Слайд 52Implications of Resistance
www.roar.apua.org

Implications of Resistancewww.roar.apua.org

Слайд 55Minimal Inhibitory Concentration (MIC)
vs.
Minimal Bactericidal Concentration (MBC)
REVIEW

Minimal Inhibitory Concentration (MIC)vs.Minimal Bactericidal Concentration (MBC)REVIEW

Слайд 56What are main targets of Antibiotics?
REVIEW

What are main targets of Antibiotics?REVIEW

Слайд 57Mechanism of Action
INHIBITION OF CELL WALL SYNTHESIS
β-Lactams
Non β-Lactams
REVIEW

Mechanism of ActionINHIBITION OF CELL WALL SYNTHESISβ-LactamsNon β-LactamsREVIEW

Слайд 58Mechanism of Action CELL WALL SYNTHESIS INHIBITORS
β-Lactam ring structure
(cont’d)
REVIEW

Mechanism of Action CELL WALL SYNTHESIS INHIBITORS β-Lactam ring structure(cont’d)REVIEW

Слайд 59 Mechanism of Action
Aminoglycosides
Macrolides
Chloramphenicol
Erythromycin
Tetracyclines
Clindamycin
INHIBITION OF PROTEIN SYNTHESIS
REVIEW

Mechanism of Action AminoglycosidesMacrolidesChloramphenicolErythromycinTetracyclinesClindamycin INHIBITION OF PROTEIN SYNTHESISREVIEW

Слайд 60Mechanism of Action
INHIBITION OF NUCLEIC ACID SYNTHESIS
Rifampin
Metronidazole
Quinolones and

fluoroquinolones
REVIEW

Mechanism of Action INHIBITION OF NUCLEIC ACID SYNTHESISRifampinMetronidazoleQuinolones and fluoroquinolonesREVIEW

Слайд 61Mechanism of Action
DISRUPTION OF CELL MEMBRANES
Polymyxins
Colistin
REVIEW

Mechanism of ActionDISRUPTION OF CELL MEMBRANESPolymyxinsColistinREVIEW

Слайд 62Mechanism of Action
ANTIMETABOLITE ACTION
Sulfonamides
Trimethoprim-sulfamethoxazole
REVIEW

Mechanism of ActionANTIMETABOLITE ACTIONSulfonamides Trimethoprim-sulfamethoxazole REVIEW

Слайд 63Resistance Physiological Mechanisms
1. Lack of entry – tet, fosfomycin
2. Greater

exit
efflux pumps
tet (R factors)
3. Enzymatic inactivation
bla

(penase) – hydrolysis
CAT – chloramphenicol acetyl transferase
Aminogylcosides & transferases

REVIEW

Resistance Physiological Mechanisms1. Lack of entry – tet, fosfomycin2. Greater exit efflux pumps tet (R factors)3.

Слайд 64Resistance Physiological Mechanisms
4. Altered target
RIF – altered RNA polymerase

(mutants)
NAL – altered DNA gyrase
STR – altered ribosomal

proteins
ERY – methylation of 23S rRNA
5. Synthesis of resistant pathway
TMPr plasmid has gene for DHF reductase; insensitive to TMP

(cont’d)

REVIEW

Resistance Physiological Mechanisms4. Altered target RIF – altered RNA polymerase (mutants) NAL – altered DNA gyrase

Слайд 65Resistance to β-Lactams – Gram pos.
Mechanism of Action CELL WALL SYNTHESIS

INHIBITORS
(cont’d)
REVIEW

Resistance to β-Lactams – Gram pos.Mechanism of Action CELL WALL SYNTHESIS INHIBITORS (cont’d)REVIEW

Слайд 66Resistance to β-Lactams – Gram neg.

Mechanism of Action CELL WALL SYNTHESIS

INHIBITORS
(cont’d)
REVIEW

Resistance to β-Lactams – Gram neg.Mechanism of Action CELL WALL SYNTHESIS INHIBITORS (cont’d)REVIEW

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