Drugs, Microbes, Host The Elements of Chemotherapy Antibiotics - Still Miracle Drugs

Paul Ehrlichs 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)

Chemical structure of penicillins

The R group is responsible for the activity of the drug, and cleavage of the beta-lactam ring will render the drug inactive.

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 structure of cephalosporins

The different
R groups allow for versatility and improved effectiveness.

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

Inhibitors of Protein Synthesis

Broad spectrum, toxicity problems Examples
Aminoglycosides: Streptomycin, neomycin, gentamycin Tetracyclines Macrolides: Erythromycin Chloramphenicol

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

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

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

Mechanisms of Antibiotic Resistance

Enzymatic destruction of drug Prevention of penetration of drug Alteration of drug's target site Rapid ejection of the drug

Antimicrobial Resistance
Relative or complete lack of effect of antimicrobial against a previously susceptible microbe

Antibiotic Resistance

Figure 20.20

Antibiotic Resistance
Intermicrobial transfer of plasmids containing resistance genes (R factors) occurs by conjugation, transformation,and transduction

Figure 20.20

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

The Future of Chemotherapeutic Agents

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