Chemotherapeutic Agents and Their Development

Chemotherapeutic Agents

• Chemical agents used to treat disease
• Destroy pathogenic microbes or inhibit their growth in the host
• Most are antibiotics
• Are microbial products or their derivatives that kill susceptible microbes or inhibit their growth

The Development of Chemotherapy

• Paul Ehrlich (1904) developed the concept of selective toxicity
• Identified dyes that effectively treated African sleeping sickness
• Sahachiro Hato (1910), working with Ehrlich, identified arsenic compounds that effectively treated syphilis
• Gerhard Domagk, and Jacques and Therese Trefouel (1935) discovered sulfonamides and sulfa drugs

Penicillin

• First discovered by Ernest Duchesne (1896), but the discovery was lost
• Accidentally discovered by Alexander Fleming (1928)
• Observed penicillin activity on contaminated plates
• Did not think it could be developed further
• Effectiveness demonstrated by Florey, Chain, and Heatley (1939)

Later Discoveries

• Streptomycin, an antibiotic active against tuberculosis, was discovered by Selman Waksman (1944)
• Nobel Prize awarded to Waksman in 1952 for this discovery
• By 1953, chloramphenicol, terramycin, neomycin, and tetracycline were isolated

General Characteristics of Antimicrobial Drugs

• Selective toxicity - the ability of a drug to kill or inhibit a pathogen while damaging the host as little as possible.
• Therapeutic dose - the drug level required for effective clinical treatment
• Toxic dose - the drug level at which the drug becomes too toxic for the patient (causing side effects).
• Therapeutic index - the ratio of the toxic dose to the therapeutic dose; a higher index indicates the drug is more selective

Dilution Susceptibility Tests

• Involves inoculating media with different drug concentrations.
• Broth or agar with the lowest concentration showing no growth is the MIC
• Tubes showing no growth in broth can be subcultured into a drug-free medium
• Broth from which the microbe can't be recovered is the MLC

Disk Diffusion Tests

• Disks impregnated with specific drugs are placed on agar plates inoculated with the test microbe.
• Drug diffuses from the disk into the agar, setting up a concentration gradient.
• Clear zones (no growth) around disks are observed

Kirby-Bauer Method

• Standardized method for carrying out disk diffusion tests.
• Sensitivity and resistance are determined using tables correlating the zone diameter with the degree of microbial resistance.
• Table values are plotted and used to estimate if the drug concentration in the body will be effective.

Measuring Antimicrobial Sensitivity, E Test

• Similar to disk diffusion tests but uses strips instead of disks.
• E-test strips contain a gradient of an antibiotic.
• The intersection of the elliptical zone of inhibition with the strip indicates the MIC.

Measurement of Drug Concentrations in the Blood

• Concentration of drug at the infection site must be above the MIC to be effective.
• Microbiological, chemical, immunological, enzymatic, or chromatographic assays can determine drug concentration in the blood.

Mechanism of Action of Antimicrobial Agents

• Can impact pathogens by targeting functions necessary for reproduction or survival.
• Targeted function is specific to the pathogen → higher therapeutic index

Modes of Antimicrobial Action

• Inhibition of cell wall synthesis (Penicillins, cephalosporins, bacitracin, vancomycin)
• Inhibition of protein synthesis (chloramphenicol, erythromycin, tetracyclines, streptomycin)
• Inhibition of nucleic acid replication and transcription (quinolones, rifampin)
• Injury to the plasma membrane (polymyxin B)
• Inhibition of the synthesis of essential metabolites (sulfanilamides, trimethoprim)

Competitive Inhibitors (Sulfonamides)

• Inhibit folic acid synthesis
• Broad-spectrum

Factors Influencing the Effectiveness of Antimicrobial Drugs

• Ability of drug to reach the site of infection
• Susceptibility of the pathogen to the drug
• Drug ability to reach concentrations in the body that exceed the MIC of the pathogen

Ability of Drug to Reach Site of Infection

• Depends partly on the mode of administration
• Oral drugs may be destroyed by stomach acid
• Topical drugs target the skin's surface
• Parenteral routes (injections) are non-oral and the drug may be excluded by blood clots or necrotic tissue

Inhibitors of Cell Wall Synthesis (Penicillins)

• Most are 6-aminopenicillanic acid derivatives
• Differ in side chains attached to the amino group
• Crucial feature is the β-lactam ring (essential for bioactivity)
• Many penicillin-resistant organisms produce β-lactamase which hydrolyzes the bond in the β-lactam ring

Mode of Action of Penicillins

• Blocks the enzyme that catalyzes transpeptidation (cross-link formation in peptidoglycan)
• Prevents synthesis of complete cell walls leading to cell lysis
• Acts only on growing bacteria that are synthesizing new peptidoglycan

Cephalosporins

• Structurally and functionally similar to penicillins
• Broad-spectrum antibiotics suitable for patients allergic to penicillin
• Four categories based on their spectrum of activity

Vancomycin and Teicoplanin

• Glycopeptide antibiotics
• Inhibit cell wall synthesis
• Important for treating antibiotic-resistant staphylococcal and enterococcal infections
• Previously considered a last resort drug due to the risk of resistance

Protein Synthesis Inhibitors

• Many antibiotics bind specifically to the bacterial ribosome (30S or 50S subunit).
• Other antibiotics inhibit steps in protein synthesis (aminoacyl-tRNA binding, peptide bond formation, mRNA reading, translocation).

Nucleic Acid Synthesis Inhibition

• Variety of mechanisms to block DNA replication (inhibition of DNA polymerase, DNA helicase), and transcription (inhibition of RNA polymerase)
• Drugs are not selective because bacteria and eukaryotes do not greatly differ in how they synthesize nucleic acids

Antifungal Agents

• Nystatin (mycostatin): Treats yeasts
• Griseofulvin (Grisactin): Treats dermatophyte fungi
• Amphotercin B (Fungizone): Treats systemic fungi

Superinfection

• Development and spread of drug-resistant pathogens, potentially caused by drug treatment; destroys drug-sensitive strains
• Example: pseudomembranous enterocolitis - treatment with antibiotics kills intestinal flora, leaving Clostridium difficile to flourish and produce a toxin

Preventing Emergence of Drug Resistance

• Use drugs in high concentrations when required
• Administer two or more drugs simultaneously when needed
• Use drugs only when necessary/indicated
• Continued development of new drugs
• Use bacteriophages to treat bacterial disease

Antiviral Drugs

• Relatively few because it's hard to specifically target viral replication

Amantadine

• Used to prevent influenza infections
• Blocks penetration and uncoating of the influenza virus

Other Antiviral Agents

• Acyclovir, Foscarnet, Cidofovir: Inhibit herpes virus enzymes involved in DNA and RNA synthesis and function. Broad-spectrum anti-DNA virus drugs inhibit viral DNA polymerases and affect papovaviruses, adenoviruses, herpesviruses, other viruses, etc.

Anti-HIV Drugs

• Reverse transcriptase (RT) inhibitors (nucleoside and non-nucleoside RT inhibitors) mimic peptide bonds normally targeted by proteases)
• Protease inhibitors, which mimic peptide bonds attacked by HIV proteases
• Fusion inhibitors, prevent HIV entry into cells

Explore the history and discovery of chemotherapeutic agents, including antibiotics and sulfa drugs. Learn about key figures such as Paul Ehrlich and Alexander Fleming, who played significant roles in advancing treatment methods for infectious diseases. Test your knowledge of how these chemical agents work and their impact on medicine.