drugs, microbes, host – the elements of chemotherapy antibiotics - still miracle drugs
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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 ToxicityMechanisms 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
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
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
• 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
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 ResistanceIntermicrobial 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
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
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
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