antibiotics lecture may 2010
TRANSCRIPT
Antimicrobial Drugs
Fading Miracle?
BLS 206 Lecture
Hoza, A . S
Ehrlich’s Magic Bullets
• 1906: Paul
Ehrlich discovered
Salvarsan 606
• 1930s: sulfa drugs
discovered
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 activity
Level 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 synergism
Combination of antibiotics have enhanced activity
when tested together compared with each antibiotic
alone (e.g. 2 + 2 = 6)
e.g. ampicillin+gentamicin in entercoccal carditis
Additive effect
Combination of antibiotics has an additive effect
(e.g. 2 + 2 = 4)
e.g. combination of two ß-lactam antibiotics
Antibiotic 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 antibiotics
Penicillins, cephalosporins and cephamycins,
carbapenems and monobactams, ß-lactamase inhibitor/ß-
lactam combinations
Glycopeptides
Vancomycin
Polypeptides
Bacitracin, polymyxins
Drugs used for treatment of mycobacterial infections
Isoniazid, 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
Tetracyclines
Acting at 50S ribosomesChloramphenicol
Macrolides
Clindamycin
Streptogramins
Oxazolidones
3. Inhibition of nucleic acid synthesis
Acting on DNA replication
Quinolones
Metronidazole
Acting on RNA synthesis
Rifampin
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
wallGram negative cell
wall
Penicillins
Figure 20.6
Penicillinase (b Lactamase)
Figure 20.8
• Penicilinase- resistant penicillins
• Carbapenems: very broad spectrum
• Monobactam: Gram negative
• Extended- spectrum penicillins
• Penicillins + b-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 Drugs
Nucleoside 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