Antimicrobial Compounds

• Lecture 25 focuses on antimicrobial compounds.

Lecture Objectives

• It is essential to distinguish between disinfectants, antiseptics, and antibiotics.
• Describe two mechanisms by which antibiotics treat infections: cidal (kills bacteria) versus static (inhibits growth).
• Understand and define MIC (Minimum Inhibitory Concentration), MBC (Minimum Bactericidal Concentration), and MBEC (Minimum Biofilm Eradicating Concentration).
• Identify what qualities make an antibiotic effective.
• Know the benefits and potential problems associated with broad-spectrum antibiotic therapies.
• Outline the necessary steps for developing a novel compound into a new antibiotic drug.

Importance and Prevention of Exposure

• Focus on avoidance, reduction, and prevention
• Safe water involves filtration and chlorination.
• Food can be protected using Pasteurization (72°C for 15-20 seconds to delay spoilage).
• Tyndallization involves repeated steaming, while pressure cooking (autoclave) uses 121°C at 15-20 PSI for 20-60 minutes.
• Baking at 150°C (300°F) for 1-2 hours as well as ionizing irradiation are other methods.
• Irradiation is measured in Grays (Gy).
• 1 Gy equals 1 joule/kg.
• Irradiation dosage varies: 0.1 kGy for insects and parasites, 0.3-0.7 kGy for bacteria, 4.5 kGy if food is embedded, 10 kGy for viruses, and 30 kGy for spores.

Goals of Antimicrobial Therapy

• The goal is to destroy or inhibit pathogenic microorganisms so that the host immune system can combat the infection.
• Treatments should not cause more harm than the actual disease by minimizing side effects.
• The therapeutic index is the ratio of toxic dose concentration to effective dose concentration,
• Higher ratios indicate a more significant difference between toxic and effective doses.

Antimicrobial Compounds

• Any substance or drug that can kill or inhibit the growth of microbes.
• Disinfectants sterilize inanimate objects (fomites) and include formaldehyde, phenol, and bleach.
• Antiseptics are applied to the skin or used as mouthwash.
• Examples of antiseptics are iodine, rubbing alcohol, 3% H2O2, and triclosan.
• Antibiotics can be used on the outside or inside of the body, with examples like penicillin, tetracycline, and erythromycin.

Disinfectants Mode of Action

• Alcohols denature proteins
• Alkylating agents form epoxide bridges preventing protein activity.
• Halides are oxidizing agents.
• Heavy metals bind to -SH groups, denaturing proteins.
• Phenols denature proteins and disrupt cell membranes.
• QAC's disrupt cell membranes.
• UV radiation blocks DNA replication and transcription by damaging DNA.

Antiseptics

• Antiseptics often include diluted or weaker versions of disinfectants.
• This makes them safer for skin exposure.
• Examples include alcohols, hydrogen peroxide (H2O2), iodine, QACs, and weak acids like vinegar (acetic, salicylic, or sorbic acid).

Antimicrobial Susceptibility

• Bactericidal antibiotics kill bacteria and include beta-lactams and fluoroquinolones.
• Bacteriostatic antibiotics inhibit bacterial growth and depend on the status of the bacteria.
• They must synergize with the immune system.
• Examples include tetracyclines and macrolides.
• Cell wall-active antibiotics are more effective when cells are dividing.

Minimal Inhibitory Concentration (MIC)

• The lowest concentration of an antibiotic needed to inhibit microbial growth.
• E-tests determine the MIC through a predefined gradient of antibiotic concentrations on a plastic strip.

Minimal Bactericidal Concentration (MBC)

• The lowest concentration of antibiotic required to kill 99.9% of bacteria.
• This is often ten times greater than the MIC.

MBEC (Minimum Biofilm Eradicating Concentration)

• MBEC is the minimum concentration needed to prevent the regrowth of bacteria from a treated biofilm.
• This assay uses a 96-well ELISA to determine MBEC values for eight different antibiotics.
• Knowing the MBEC is important because it identifies the concentration needed to eradicate biofilm-associated infections.

Qualities of a Good Antibiotic

• A good antibiotic has a good therapeutic index, targeting pathogen cellular machinery but not hosts, and exhibiting low side effects.
• A broad spectrum of activity is helpful when the causative agent is unknown (e.g., sepsis).
• A good antibiotic generally interacts with a few molecular targets.
• This limits potential host toxicity.
• Desirable Pharmacokinetics.
• Antibiotics not distributed equally; concentrations vary.
• Some antibiotics concentrate in the kidney, effective for UTIs.
• Some drugs need the ability to cross the blood-brain barrier to treat meningitis.
• The length of time the antibiotic compound lasts depends on rates of degradation or removal.
• Liver enzymes can degrade antibiotics
• The kidney can quickly excrete compounds.

Therapeutic Index

• Therapeutic Index is the toxic dose concentration divided by the effective dose concentration.
• We want a large value difference between toxic dose and effective dose
• Beta-lactams, macrolides, and quinolones have a large Therapeutic index.
• Aminoglycosides and vancomycin have a low Therapeutic index.
• Because of this these drugs have the potential for severe toxic side effects and require close monitoring of the patient.

Antibiotics

• Benefits of antibiotics include the ability to treat symptoms before knowing the causative agent.
• Problems include promoting rapid resistance and disruption of native flora.

Drug Development

• Drug development includes identifying a screen compound for activity and determining the activity spectrum.
• Good ADMET is required using rodent models
• Is resistance a problem?
• Assess the potential for disruption of normal microflora,
• Multiple phases of human trials (I, II, III).
• Development cost is in the billions.