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D- Chemotherapy of Bacterial Infections
~~~~~~~~Antibiotics
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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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Impact of Modern Healthcare on Life Expectancy
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History
Paul Ehrlich“Magic Bullet”
Chemicals with selective toxicity
ORIGIN: Selective StainsDRUG: Arsphenamine (1910)
“606”Salvarsan
NOBEL: 1908
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History(cont’d)
Gerhard Domagk Drugs are changed in the body
ORIGIN: Prontosil(Only active in vivo)
DRUG: Sulfanilamide (1935)
NOBEL: 1939
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History
Alexander Fleming Microbes make antibiotics
ORIGIN: moldy culture plateDRUG: Penicillin (1928)
NOBEL: 1945
(cont’d)
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History(cont’d)
Selman Waksman Soil Streptomyces make antibiotics comes up with definition of antibiotic
ORIGIN: Penicillin developmentDRUG: Streptomycin (1943)
NOBEL: 1952
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The Ideal Drug*1. Selective toxicity: against target pathogen but not against
host
LD50 (high) vs. MIC and/or MBC (low)
2. 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.
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Susceptibility Tests1. Broth dilution - MIC test
2. Agar dilution - MIC test
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32 ug/ml 16 ug/ml 8 ug/ml 4 ug/ml 2 ug/ml 1 ug/ml
Sub-culture to agar mediumMIC = 8 ug/mlMBC = 16 ug/ml
Minimal Inhibitory Concentration (MIC)vs.
Minimal Bactericidal Concentration (MBC)
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Susceptibility Tests
3.Agar diffusionü Kirby-Bauer Disk Diffusion Test
(cont’d)
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Susceptibility Tests“Kirby-Bauer Disk-plate test”
Diffusion depends upon:1. Concentration2. Molecular weight3. Water solubility4. pH and ionization5. Binding to agar
(cont’d)
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Susceptibility Tests“Kirby-Bauer Disk-plate test”
Zones of Inhibition (~ antimicrobial activity) depend upon:
1. pH of environment2. Media components
Agar depth, nutrients
3. Stability of drug4. Size of inoculum5. Length of incubation6. Metabolic activity of organisms
(cont’d)
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Antibiotic Mechanisms of Action
Transcription
Translation
Translation
Alteration of Cell Membrane Polymyxins Bacitracin Neomycin
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Mechanism of Action
1. ANTIMETABOLITE ACTIONSulfonamides
an analog of PABA, works by competitive inhibition
Trimethoprim-sulfamethoxazole a synergistic combination; useful against
UTIs
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Mechanism of Action ANTIMETABOLITE ACTION
(cont’d)
tetrahydrofolic acid
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Mechanism 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)
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Mechanism of Action ALTERATION OF CELL MEMBRANES
(cont’d)
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Mechanism of Action
3.INHIBITION OF PROTEIN SYNTHESIS:Steps in synthesis:
1. Initiation2. Elongation3. Translocation4. 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)
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Mechanism of ActionINHIBITION 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 acidsExamples:Gentamicin TobramycinAmikacin StreptomycinKanamycin SpectinomycinNeomycin
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Mechanism of ActionINHIBITION 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
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Mechanism of ActionINHIBITION 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
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Mechanism of ActionINHIBITION 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
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• Tetracyclines 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 ActionINHIBITION OF PROTEIN SYNTHESIS
(cont’d)
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Mechanism of Action
4. INHIBITION OF DNA/RNA SYNTHESISRifampin
binds to RNA polymerase active against gram positive cocci bactericidal for Mycobacterium used for treatment and prevention of
meningococcus
(cont’d)
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Mechanism 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
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(cont’d)
Mechanism of Action INHIBITION OF DNA/RNA SYNTHESIS
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Mechanism of Action5. CELL WALL SYNTHESIS INHIBITORS
Steps in synthesis:1. NAM-peptide made in cytoplasm2. attached to bactoprenol in cell membrane3. NAG is added4. whole piece is added to growing cell wall5. crosslinks added
• the β-Lactams• the non β-Lactams
(cont’d)
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Mechanism of Action
5.CELL WALL SYNTHESIS INHIBITORSβ-Lactam Antibiotics Penicillins Cephalosporins Carbapenems Monobactams
(cont’d)
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Mechanism of ActionCELL WALL SYNTHESIS INHIBITORS
β-Lactam ring structure
(cont’d)
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Mechanism of ActionCELL WALL SYNTHESIS INHIBITORS
Action of β-Lactam antibiotics
(cont’d)
1. Bactericidal; growing cells only
2. Drug links covalently to regulatory enzymes called PBPs (penicillin-binding proteins)
3. Blocks cross-linkage of peptidoglycan
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Mechanism of ActionCELL WALL SYNTHESIS INHIBITORS
Action of β-Lactam antibiotics(cont’d)
For E. coli> MIC
wall damage autolysins spheroplasting cell lysis
< MIC no septa filaments
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Resistance to β-Lactams – Gram pos.
Mechanism of ActionCELL WALL SYNTHESIS INHIBITORS
(cont’d)
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Resistance to β-Lactams – Gram neg.
Mechanism of ActionCELL WALL SYNTHESIS INHIBITORS
(cont’d)
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Non - β-Lactams
Mechanism of ActionCELL 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 isoniazidinhibits enzymes that catalyze cell wall
synthesisfor Mycobacterial infections
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Clinical Uses
PATHOGENS TYPICAL DRUG
Gram positivePen-ase (-)Pen-ase (+)
Penicillin G (oral or IM)Methicillin, Nafcillin
Gram negative
Enterics, etc.Pseudomonas
B. fragilis
Ampicillin, gentamicin, etc.
Ticarcillin, tobramycinClindamycin
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Clinical Uses(cont’d)
PATHOGENS TYPICAL DRUG
Mycobacterium StreptomycinIso-nicotinic hydrazide (INH)
Fungi:Cutaneous
DeepNystatin
Amphotericin B, ketoconazol
Parasites:Plasmodium
GiardiaChloroquineQuinacrine
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Resistance Physiological Mechanisms
1. Lack of entry – tet, fosfomycin2. Greater exit
efflux pumps tet (R factors)
3. Enzymatic inactivation bla (penase) – hydrolysis CAT – chloramphenicol acetyl transferase Aminogylcosides & transferases
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Resistance 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)
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Origin 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
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Origin 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)
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Plasmids
• independent replicons • circular DNA
• dispensable• several genes• drug resistance• metabolic enzymes• virulence factors
• host range• restricted or broad
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Plasmids
• size• small, non-conjugal • large, conjugal <25 kbp
• Transfer between cells:• CONJUGATION (cell to cell contact)•due to plasmid tra genes (for pili, etc)
NON-CONJUGAL• transduction •mobilization by conjugation plasmids
(cont’d)
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Implicationsof 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
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Implications 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
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Implicationsof Resistance
• www.roar.apua.org
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REVIEW
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32 ug/ml 16 ug/ml 8 ug/ml 4 ug/ml 2 ug/ml 1 ug/ml
Sub-culture to agar mediumMIC = 8 ug/mlMBC = 16 ug/ml
Minimal Inhibitory Concentration (MIC)vs.
Minimal Bactericidal Concentration (MBC)
REVIEW
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What are main targets of Antibiotics?
REVIEW
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Mechanism of Action
INHIBITION OF CELL WALL SYNTHESIS• β-Lactams• Non β-Lactams
REVIEW
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Mechanism of ActionCELL WALL SYNTHESIS INHIBITORS
β-Lactam ring structure
(cont’d)
REVIEW
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Mechanism of Action
• Aminoglycosides• Macrolides• Chloramphenicol• Erythromycin
• Tetracyclines• Clindamycin
INHIBITION OF PROTEIN SYNTHESIS
REVIEW
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Mechanism of Action
INHIBITION OF NUCLEIC ACID SYNTHESIS
Rifampin
Metronidazole
Quinolones and fluoroquinolones
REVIEW
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Mechanism of Action
DISRUPTION OF CELL MEMBRANES
Polymyxins
Colistin
REVIEW
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Mechanism of Action
ANTIMETABOLITE ACTION Sulfonamides Trimethoprim-sulfamethoxazole
REVIEW
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Resistance Physiological Mechanisms
1. Lack of entry – tet, fosfomycin2. Greater exit
efflux pumps tet (R factors)
3. Enzymatic inactivation bla (penase) – hydrolysis CAT – chloramphenicol acetyl transferase Aminogylcosides & transferases
REVIEW
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Resistance 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
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Resistance to β-Lactams – Gram pos.
Mechanism of ActionCELL WALL SYNTHESIS INHIBITORS
(cont’d)
REVIEW
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Resistance to β-Lactams – Gram neg.
Mechanism of ActionCELL WALL SYNTHESIS INHIBITORS
(cont’d)
REVIEW