antibiotics lecture may 2010
TRANSCRIPT
Antimicrobial Drugs
Fading Miracle?
BLS 206 Lecture
Hoza, A . S
Ehrlich’s Magic Bullets
• 1906: PaulEhrlich discoveredSalvarsan 606
• 1930s: sulfa drugsdiscovered
Fleming and Penicillin
TERMINOLOGIES
Chemotherapy
• The use of drugs to treat a disease
• Selective toxicity:
– A drug that kills harmful microbes without damaging the host
Terminologies
Antibacterial spectrumRange of activity of an antibiotic
A broad spectrumAntibiotic that can inhibit wide range of G- positive and G-negative bacteria e.g. Carbapenems, 3-4th generation cephalosporins, quinolones
A narrow spectrumAntibiotic that is active only against a limited number of bacteria e.g. penicillin G, 1-2nd generation cephalosporins, oxazolidone
Terminologies
Bacteriostatic activityLevel of antimicrobial activity that inhibits the
growth of bacteria
Minimum inhibitory concentration (MIC)
The lowest concentration that inhibits the growth of bacterial population
Bactericidal activity
Minimum bactericidal concentration (MBC)The lowest concentration that kills 99.9% of
the bacterial population
Antibiotic synergismCombination of antibiotics have enhanced activity
when tested together compared with each antibioticalone (e.g. 2 + 2 = 6)e.g. ampicillin+gentamicin in entercoccal carditis
Additive effectCombination of antibiotics has an additive effect (e.g. 2 + 2 = 4)
e.g. combination of two ß-lactam antibioticsAntibiotic antagonism
Combination in which the activity of one antibiotic interferes with the activity of the other (e.g. 2 + 2 < 4)
Antibiotic combinations
Effects of Combinations of Drugs
• Synergism occurs when the effect of two drugs together is greater than the effect of either alone.
• Antagonism occurs when the effect of two drugs together is less than the effect of either alone.
Effects of Combinations of Drugs
Combined antibacterial therapy
Antibiotic/Antimicrobial
• Antibiotic: – Chemical produced by a microorganism that
kills or inhibits the growth of another microorganism
• Antimicrobial agent: – Chemical that kills or inhibits the growth of
microorganisms
Antimicrobial Agents• Disinfectant:
•antimicrobial agent used only on inanimate objects
• Chemotherapeutic agent: •antimicrobial agent that can be used internally
• Bactericidal: •agent that kills bacteria
• Bacteriostatic: •agent that inhibits the growth of bacteria
Microbial Sources of Antibiotics
Antibiotic Spectrum of Activity
• No antibiotic is effective against all microbes
Mechanisms of Antimicrobial Action
• Bacteria have their own enzymes for– Cell wall formation
– Protein synthesis
– DNA replication
– RNA synthesis
– Synthesis of essential metabolites
Mechanisms of Antimicrobial Action
• Viruses use host enzymes inside host cells
• Fungi and protozoa have own eukaryotic enzymes
• The more similar the pathogen and host enzymes, the more side effects the antimicrobials will have
Modes of Antimicrobial Action
Basic mechanisms of antibiotics
Basic mechanisms of antibiotic action(1) Disruption of bacterial cell wall
ß-lactam antibioticsPenicillins, cephalosporins and cephamycins, carbapenems and monobactams, ß-lactamase inhibitor/ß-lactam combinations
GlycopeptidesVancomycin
PolypeptidesBacitracin, polymyxins
Drugs used for treatment of mycobacterial infectionsIsoniazid, ethinamide, ethambutol, cycloserine
Bacterial cell wall of G+ (A) and G- (B) bacteria
Gram-positive and Gram-negative bacteria
2. Inhibition of protein synthesis
Acting at 30S ribosomesAminoglycosides
TetracyclinesActing at 50S ribosomes
Chloramphenicol
Macrolides
Clindamycin
Streptogramins
Oxazolidones
3. Inhibition of nucleic acid synthesis
Acting on DNA replicationQuinolones
Metronidazole
Acting on RNA synthesisRifampin
Rifabutin
4. Antimetabolites
Sulfonamides
Dapsone
Trimethoprim
Paraaminosalicylic acid
Antimicrobial Agents
Antimicrobial Agents
Antimicrobial Agents
• Penicillin (over 50 compounds)
– Share 4-sided ring (ß lactam ring)
• Natural penicillins• Narrow range of action
• Susceptible to penicillinase (ß lactamase)
Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis
Prokaryotic Cell Walls
Gram positive cell wall
Gram negative cell wall
Penicillins
Figure 20.6
Penicillinase ( Lactamase)
Figure 20.8
• Penicilinase- resistant penicillins
• Carbapenems: very broad spectrum
• Monobactam: Gram negative
• Extended- spectrum penicillins
• Penicillins + -lactamase inhibitors
Semisynthetic Penicillins
• Cephalosporins– 2nd, 3rd, and 4th
generations more effective against gram-negatives
Other Inhibitors of Cell Wall Synthesis
Figure 20.9
• Polypeptide antibiotics– Bacitracin
• Topical application
• Against gram-positives
– Vancomycin• Glycopeptide
• Important "last line" against antibiotic resistant S. aureus
Other Inhibitors of Cell Wall Synthesis
Other Inhibitors of Cell Wall Synthesis
• Antibiotics effective against Mycobacteria:
– interfere with mycolic acid synthesis or incorporation
– Isoniazid (INH)
– Ethambutol
• Broad spectrum, toxicity problems• Examples
– Chloramphenicol (bone marrow)
– Aminoglycosides: Streptomycin, neomycin, gentamycin (hearing, kidneys)
– Tetracyclines (Rickettsias & Chlamydia; GI tract)
– Macrolides: Erythromycin (gram +, used in children)
Inhibitors of Protein Synthesis
• Polymyxin B (Gram negatives)
– Topical
– Combined with bacitracin and neomycin (broad spectrum) in over-the-counter preparation
Injury to the Plasma Membrane
• Rifamycin– Inhibits RNA synthesis
– Antituberculosis
• Quinolones and fluoroquinolones– Ciprofloxacin
– Inhibits DNA gyrase
– Urinary tract infections
Inhibitors of Nucleic Acid Synthesis
– Sulfonamides (Sulfa drugs)• Inhibit folic acid synthesis
• Broad spectrum
Competitive Inhibitors
Figure 5.7
Antifungal Drugs
• Fungi are eukaryotes
• Have unique sterols in their cell walls
• Pathogenic fungi are often outside the body
Antiviral Drugs
• Viruses are composed of nucleic acid, protein capsid, and host membrane containing virus proteins
• Viruses live inside host cells and use many host enzymes
• Some viruses have unique enzymes for DNA/RNA synthesis or protein cutting in virus assembly
Figure 20.16a
Antiviral DrugsNucleoside and Nucleotide Analogs
Figure 20.16a
Figure 20.16b, c
Analogs Block DNA Synthesis
• Inhibit assembly
– Indinavir (HIV)
• Inhibit attachment– Zanamivir (Influenza)
• Inhibit uncoating
– Amantadine (Influenza)
Antiviral Drugs Enzyme Inhibitors
• Interferons – prevent spread of viruses to new cells (Viral
hepatitis)
• Natural products of the immune system in viral infections
Antiviral Drugs Enzyme Inhibitors
Antiprotozoan Drugs
• Protozoa are eukaryotic cells
• Many drugs are experimental and their mode of action is unknown
Antihelminthic Drugs
• Helminths are macroscopic multicellular eukaryotic organisms: – tapeworms,– roundworms,– pinworms,– hookworms
• Prevent ATP generation (Tapeworms)
• Alters membrane permeability (Flatworms)
• Neuromuscular block (Intestinal roundworms)
• Inhibits nutrient absorption (Intestinal roundworms)
• Paralyzes worm (Intestinal roundworms)
Antihelminthic Drugs
Measuring Antimicrobial Sensitivity
• E Test
• MIC: Minimal inhibitory concentration
Measuring Antimicrobial Sensitivity: Disk Diffusion
Penicillin