Antimicrobial Drugs
Fading Miracle?
Ehrlich’s Magic Bullets
Fleming and Penicillin
Chemotherapy
- The use of drugs to treat a disease
- Selective toxicity: A drug that kills harmful microbes without damaging the host
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
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
Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis
- Penicillin (over 50 compounds)
Share 4-sided ring (b lactam ring)
- Narrow range of action
- Susceptible to penicillinase (b lactamase)
Prokaryotic Cell Walls
Semisynthetic Penicillins
- Penicilinase-resistant penicillins
- Carbapenems: very broad spectrum
- Monobactam: Gram negative
- Extended-spectrum penicillins
- Penicillins + -lactamase inhibitors
Other Inhibitors of Cell Wall Synthesis
- Cephalosporins
- 2nd, 3rd, and 4th generations more effective against gram-negatives
Other Inhibitors of Cell Wall Synthesis
Polypeptide antibiotics
Bacitracin
Topical application
Against gram-positives
Vancomycin
Glycopeptide
- Important "last line" against antibiotic resistant S. aureus
- Antibiotics effective against Mycobacteria: interfere with mycolic acid synthesis or incorporation
- Isoniazid (INH)
- Ethambutol
Inhibitors of Protein Synthesis
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)
Injury to the Plasma Membrane
Polymyxin B (Gram negatives)
Topical
Combined with bacitracin and neomycin (broad spectrum) in over-the-counter preparation
Inhibitors of Nucleic Acid Synthesis
Rifamycin
Inhibits RNA synthesis
Antituberculosis
Quinolones and fluoroquinolones
Ciprofloxacin
Inhibits DNA gyrase
Urinary tract infections
Competitive Inhibitors
Sulfonamides (Sulfa drugs)
Inhibit folic acid synthesis
Broad spectrum
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
Antiviral Drugs Nucleoside and Nucleotide Analogs
Analogs Block DNA Synthesis
Antiviral Drugs Enzyme Inhibitors
Inhibit assembly
Indinavir (HIV)
Inhibit attachment
Zanamivir (Influenza)
Inhibit uncoating
Amantadine (Influenza)
Interferons prevent spread of viruses to new cells (Viral hepatitis)
Natural products of the immune system in viral infections
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)
Measuring Antimicrobial Sensitivity
E Test
MIC: Minimal inhibitory concentration
Measuring Antimicrobial Sensitivity: Disk Diffusion
Antibiotic Resistance
Antimicrobial Resistance
Relative or complete lack of effect of antimicrobial against a previously susceptible microbe
Increase in MIC
Mechanisms of Antibiotic Resistance
Enzymatic destruction of drug
Prevention of penetration of drug
Alteration of drug's target site
Rapid ejection of the drug
Antibiotic Selection for Resistant Bacteria
What Factors Promote Antimicrobial Resistance?
Exposure to sub-optimal levels of antimicrobial
Exposure to microbes carrying resistance genes
Inappropriate Antimicrobial Use
Prescription not taken correctly
Antibiotics for viral infections
Antibiotics sold without medical supervision
Spread of resistant microbes in hospitals due to lack of hygiene
Lack of quality control in manufacture or outdated antimicrobial
Inadequate surveillance or defective susceptibility assays
Poverty or war
Use of antibiotics in foods
Antibiotics in Foods
Antibiotics are used in animal feeds and sprayed on plants to prevent infection and promote growth
Multi drug-resistant Salmonella typhi has been found in 4 states in 18 people who ate beef fed antibiotics
Consequences of Antimicrobial Resistance
Infections resistant to available antibiotics
Increased cost of treatment
Multi-Drug Resistant TB
MRSA “mer-sah”
Methicillin-Resistant Staphylococcus aureus
Most frequent nosocomial (hospital-acquired) pathogen
Usually resistant to several other antibiotics
Vancomycin Resistant Enterococci
Proposals to Combat Antimicrobial Resistance
Speed development of new antibiotics
Track resistance data nationwide
Restrict antimicrobial use
Direct observed dosing (TB)
Proposals to Combat Antimicrobial Resistance
Use more narrow spectrum antibiotics
Use antimicrobial cocktails
The Future of Chemotherapeutic Agents
Antimicrobial peptides
Broad spectrum antibiotics from plants and animals
Squalamine (sharks)
Protegrin (pigs)
Magainin (frogs)
Antisense agents
Complementary DNA or peptide nucleic acids that binds to a pathogen's virulence gene(s) and prevents transcription
