Ch 10 Antimicrobial Drugs: Mechanisms, Effectiveness, and Resistance

Ch 10 - Controlling Microbial Growth in the Body

Contributions to Antimicrobial Development

Several scientists have played pivotal roles in the discovery and development of antimicrobial drugs, which are essential for treating infectious diseases.

• Paul Ehrlich: Developed the concept of the "magic bullet" and discovered Salvarsan, the first effective treatment for syphilis.

• Alexander Fleming: Discovered penicillin, the first true antibiotic, from the mold Penicillium notatum.

• Gerhard Domagk: Discovered Prontosil, a sulfa drug effective against bacterial infections.

Types of Antimicrobials

Antimicrobials are classified based on their origin and chemical modification.

• Antibiotics: Naturally produced by microorganisms (e.g., bacteria, fungi).

• Semisynthetic drugs: Chemically modified derivatives of natural antibiotics to improve efficacy or reduce side effects.

• Synthetic drugs: Completely synthesized in the laboratory, not derived from natural sources.

Principle of Selective Toxicity

Selective toxicity refers to the ability of a drug to target pathogens without harming the host.

• Drugs exploit differences between microbial and host cells (e.g., cell wall, ribosomes).

• Ideal antimicrobials have high toxicity to microbes and low toxicity to humans.

Mechanisms of Antimicrobial Action

Antimicrobial drugs affect pathogens through six main mechanisms:

• Inhibition of cell wall synthesis

• Inhibition of protein synthesis

• Disruption of cytoplasmic membranes

• Inhibition of metabolic pathways

• Inhibition of nucleic acid synthesis

• Prevention of virus attachment, entry, or uncoating

Inhibition of Cell Wall Synthesis

Drugs targeting cell wall synthesis prevent proper formation of peptidoglycan in bacteria or disrupt fungal cell walls.

• Beta-lactams (e.g., penicillins, cephalosporins): Block cross-linking of peptidoglycan.

• Vancomycin: Inhibits peptidoglycan synthesis by binding to D-Ala-D-Ala termini.

• Bacitracin: Interferes with transport of peptidoglycan precursors.

• Echinocandins: Inhibit fungal cell wall synthesis by blocking β-glucan formation.

Inhibition of Protein Synthesis

These drugs target microbial ribosomes, which differ from eukaryotic ribosomes.

• Aminoglycosides (e.g., streptomycin): Cause misreading of mRNA.

• Tetracyclines: Block tRNA attachment to the ribosome.

• Chloramphenicol: Inhibits peptide bond formation.

• Macrolides (e.g., erythromycin): Block translocation of ribosome.

• Oxazolidinones: Prevent formation of the initiation complex.

• Lincosamides: Inhibit peptide bond formation.

• Mupirocin: Specifically inhibits isoleucyl-tRNA synthetase, preventing incorporation of isoleucine into proteins.

Disruption of Cytoplasmic Membranes

Drugs in this category damage the integrity of microbial membranes, leading to cell death.

• Polymyxins: Bind to LPS and phospholipids in Gram-negative bacteria, disrupting membrane.

• Azoles and allylamines: Inhibit ergosterol synthesis in fungal membranes.

Inhibition of Metabolic Pathways

These drugs block essential metabolic reactions in microbes.

• Sulfonamides: Inhibit folic acid synthesis by acting as analogs of para-aminobenzoic acid (PABA).

• Trimethoprim: Inhibits dihydrofolate reductase, blocking folic acid production.

• Analog: A compound structurally similar to another, used to block or mimic metabolic pathways.

• Antiviral drugs: Some inhibit viral enzymes or block viral metabolism (e.g., protease inhibitors).

Inhibition of Nucleic Acid Synthesis

These drugs interfere with DNA or RNA synthesis, preventing replication and transcription.

• Nucleotide/nucleoside analogs: Mimic normal nucleotides, causing chain termination (e.g., AZT for HIV).

• Quinolones (e.g., ciprofloxacin): Inhibit DNA gyrase, blocking DNA replication.

• Rifamycins: Bind to RNA polymerase, inhibiting transcription.

• Reverse transcriptase inhibitors: Block viral reverse transcriptase, preventing viral DNA synthesis.

Prevention of Virus Attachment, Entry, or Uncoating

Some drugs prevent viruses from attaching to or entering host cells.

• Attachment antagonists: Block viral proteins from binding to host receptors.

• Entry inhibitors: Prevent fusion of viral envelope with host membrane.

• Uncoating inhibitors: Block viral uncoating, preventing release of viral genome.

Spectrum of Action

Antimicrobial drugs vary in their range of activity.

• Narrow-spectrum drugs: Target specific types of microbes; less likely to disrupt normal flora.

• Broad-spectrum drugs: Affect a wide range of microbes; may cause more side effects, such as superinfections.

Effectiveness Testing

Several laboratory tests assess the effectiveness of antimicrobial drugs.

• Diffusion susceptibility test (Kirby-Bauer): Measures zone of inhibition around drug disks.

• Etest: Uses a strip with a gradient of drug concentration to determine minimum inhibitory concentration (MIC).

• MIC test: Determines the lowest concentration of drug that inhibits visible growth.

• MBC test: Determines the lowest concentration of drug that kills the microbe.

Routes of Administration

Antimicrobials can be administered in various ways, each with advantages and disadvantages.

• Oral: Convenient, but absorption may be variable.

• Intramuscular (IM): Rapid absorption, but painful.

• Intravenous (IV): Immediate effect, but requires medical supervision.

Safety and Side Effects

Antimicrobial therapy can cause several types of side effects.

• Toxicity: Damage to organs (e.g., liver, kidneys).

• Allergic reactions: Immune response to drug (e.g., anaphylaxis).

• Disruption of normal microbiota: Can lead to secondary infections (e.g., Clostridioides difficile).

• Therapeutic index: Ratio of toxic dose to effective dose. $TI = \frac{TD_{50}}{ED_{50}}$

• Therapeutic range: The concentration range in which the drug is effective without being toxic.

Development of Resistance

Microbial populations can develop resistance to antimicrobial drugs over time.

• Resistance arises through mutation or acquisition of resistance genes.

• R plasmids: Carry genes for drug resistance and can be transferred between bacteria.

Mechanisms of Resistance

Microorganisms can resist drugs through several mechanisms:

• Enzymatic destruction or inactivation of drug

• Alteration of drug target

• Decreased uptake of drug

• Increased efflux of drug

• Bypass of metabolic pathway

• Protection of target site

• Biofilm formation

Spread of Resistance Genes

Resistance genes can be spread between bacteria by:

• Conjugation: Transfer of plasmids via direct cell contact.

• Transformation: Uptake of free DNA from the environment.

• Additional info: Transduction (transfer by bacteriophages) is another mechanism.

Multiple Resistance and Cross Resistance

Resistance can be classified as follows:

• Multiple resistance: Resistance to several unrelated drugs.

• Cross resistance: Resistance to similar drugs due to a single mechanism.

Retarding Resistance

Strategies to slow the development of resistance include:

• Use drugs only when necessary

• Use combinations of drugs

• Ensure proper dosage and duration

• Develop new drugs and alternative therapies

Summary Table: Mechanisms of Antimicrobial Action

Mechanism	Example Drugs	Target
Cell Wall Synthesis Inhibition	Penicillins, Vancomycin, Echinocandins	Peptidoglycan, β-glucan
Protein Synthesis Inhibition	Aminoglycosides, Tetracyclines, Macrolides, Mupirocin	Ribosomes
Membrane Disruption	Polymyxins, Azoles	Cytoplasmic membrane
Metabolic Pathway Inhibition	Sulfonamides, Trimethoprim	Folic acid synthesis
Nucleic Acid Synthesis Inhibition	Quinolones, Rifamycins, Nucleoside analogs	DNA/RNA synthesis
Virus Attachment/Entry Prevention	Attachment antagonists, Entry inhibitors	Viral proteins, host receptors