Drugs, Microbes, Host – The Elements of Chemotherapy

Drugs, Microbes, Host –
The Elements of Chemotherapy
Antibiotics - Still Miracle Drugs
Paul Ehrlich’s Magic Bullets
Salvarsan No. 606
Fleming and Penicillin
Antibiotics
Topics
- Antimicrobial Therapy
- Selective Toxicity
- Survey of Antimicrobial Drugs
- Microbial Drug Resistance
- Drug and Host Interaction






Antibiotics
Naturally occurring antimicrobials
Metabolic products of bacteria and fungi
Reduce competition for nutrients and space
Bacteria that produce them:
Streptomyces, Bacillus,
Molds
Penicillium, Cephalosporium
Selective Toxicity
Drugs that specifically target microbial processes, and not the human host cellular processes.
Selective Toxicity
Mechanisms and sites
Mechanism of action
Bacterial cell wall
Nucleic acid synthesis
Protein synthesis
Cell membrane
Folic acid synthesis
Cell wall synthesis
Bactericidal
Penicillin and cephalosporins – binds and blocks peptidases involved in cross-linking the glycan molecules
Vancomycin – hinders peptidoglycan elongation
Cycloserine – inhibits the formation of the basic peptidoglycan subunits

Antibiotics weaken the cell wall, and cause the cell to lyse.
The mechanism of action of penicillins and cephalosporins.
Penicillin
Penicillin chrysogenum
A diverse group (1st, 2nd , 3rd generations)
Natural (penicillin G and V)
Semisynthetic (Ampicillin, Carbenicillin)
Structure
Thiazolidine ring
Beta-lactam ring
Variable side chain (R group)
The R group is responsible for the activity of the drug, and cleavage of the beta-lactam ring will render the drug inactive.
Chemical structure of penicillins
Penicillinase (b Lactamase)
Cephalosporin
Cephalosporium acremonium (mold)
Widely administered today
Diverse group (natural and semisynthetic)
1st, 2nd, and 3rd generations
Structure
similar to penicillin except
Main ring is different
Two sites for R groups
The different R groups allow for versatility
and improved effectiveness.
The structure
of cephalosporins
Inhibition of Protein synthesis
Aminoglycosides
Bind to the 30S ribosome
Causes Misreading of mRNA
Tetracyclines
Block attachment of tRNA
Chloramphenicol
Binds to the 50S ribosome
Prevents peptide bond formation
Broad spectrum, toxicity problems
Examples
Aminoglycosides: Streptomycin, neomycin, gentamycin
Tetracyclines
Macrolides: Erythromycin
Chloramphenicol
Inhibitors of Protein Synthesis
Aminoglycosides
From Streptomyces
Inhibit protein synthesis
Streptomyces synthesizes many different antibiotics such as aminoglycosides, tetracycline, chloramphenicol, and erythromycin.
Tetracycline
Inhibits proteins synthesis
Broad spectrum and low cost
Commonly used to treat sexually transmitted diseases
Minor side effect – gastrointestinal disruption
Erythromycin
Inhibits protein synthesis
Broad-spectrum
Commonly used as prophylactic drug prior to surgery
Side effects - low toxicity
Chloramphenicol
Inhibits protein synthesis
Broad-spectrum
Treat typhoid fever, brain abscesses
Rarely used now due to side effects – aplastic anemia
Aminoglycoside
Sites of inhibition on the procaryotic ribosome
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
Folic acid synthesis
Sulfonamides (sulfa drug) and trimethoprim
Analogs
Competitive inhibition of enzymes
Prevents the metabolism of DNA, RNA, and amino acid
Sulfonamides compete with PABA for the active site on the enzyme.
The sulfonamide Sulfamethoxazole is commonly used in combination with trimethoprim
Antiviral
Increasing types of drugs becoming available
However, it is difficult to maintain selective toxicity
Effective drugs – target viral replication cycle
Entry
Nucleic acid synthesis
Assembly/release
Interferon – genetically engineered antiviral protein from a human gene
Antiviral drug structures and their unique
modes of action.
Antiviral drug structures and their unique
modes of action.
Antiviral drug structures and their unique
modes of action.
Other types of antimicrobials
Antifungal – ketoconizole
Antiprotozoan – metronidazole
Treat giardia
Antimalarial – Quinine
malaria
Antihelminthic – mebendazole
Tapeworms, roundworms
Enzymatic destruction of drug
Prevention of penetration of drug
Alteration of drug`s target site
Rapid ejection of the drug
Mechanisms of Antibiotic Resistance
Antimicrobial Resistance
Relative or complete lack of effect of antimicrobial against a previously susceptible microbe
Figure 20.20
Antibiotic Resistance
Figure 20.20
Antibiotic Resistance
Intermicrobial transfer of plasmids containing resistance genes (R factors) occurs by conjugation, transformation,and transduction
What Factors Promote Antimicrobial Resistance?
Exposure to sub-optimal levels of antimicrobial
Inappropriate use
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
Inappropriate Antimicrobial Use
Inadequate surveillance or defective susceptibility assays
Poverty or war
Use of antibiotics in foods
Lack of quality control in manufacture or outdated antimicrobial
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
Antibiotic Drug and Host Interaction
Toxicity to organs
Allergic reactions
Suppress/alter microflora
Effective drugs
Tetracycline treatments
can cause teeth discoloration.
Disrupting the normal flora in the intestine can result in superinfections.
Finding an effective drug for trreatment
Identify infectious agent
Perform sensitivity testing
Often the Minimum Inhibitory Concentration (MIC) is determined
The Kirby-Bauer Test.
Sensitivity test such as the Kirby-Bauer Test can be used to determine the effectiveness of a drug by measuring the zone of inhibition.
Consequences of Antimicrobial Resistance
Infections resistant to available antibiotics
Increased cost of treatment
Multi-Drug Resistant TB
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
Antimicrobial peptides
Broad spectrum antibiotics from plants and animals
Squalamine (sharks)
Protegrin (pigs)
Magainin (frogs)
The Future of Chemotherapeutic Agents
Antisense agents
Complementary DNA or peptide nucleic acids that binds to a pathogen`s virulence gene(s) and prevents transcription
The Future of Chemotherapeutic Agents