Chapter 10: Controlling Microbial Growth in the Body: Antimicrobial Drugs (Vocabulary Flashcards)

History

• Paul Ehrlich – “Magic bullets”

  • Concept: molecules that bind to receptors on germs and selectively kill pathogens

  • Early idea of chemotherapy using arsenic compounds that killed microbes but were toxic to humans

• Alexander Fleming – Penicillin released from Penicillium

  • Initially not readily available

• Gerhard Domagk – Discovered sulfanilamide

• Selman Waksman – Isolated and characterized antibiotics

• Antimicrobial agents produced naturally by organisms

• Figure 10.1: Antibiotic effect of the mold Penicillium chrysogenum

• Semisynthetics – Chemically altered antibiotics that are more effective than naturally occurring ones

• Synthetics – Antimicrobials completely synthesized in a lab

• Selective Toxicity – An effective antimicrobial agent is more toxic to the pathogen than to the host

• Antibacterial – A common term; most effective antimicrobial type; highlights differences between prokaryotic and eukaryotic cells

• References to related figures and tables (e.g., Table 10.1, Figure 10.1)

Antimicrobial Agents: Classifications

• Natural antimicrobials produced by organisms

• Semisynthetics – chemically modified natural antibiotics with improved properties

• Synthetics – fully laboratory-synthesized antimicrobials

• Selective Toxicity – toxicity greater to pathogen than to host

• Antibacterial drugs – broad or narrow in spectrum; terminology emphasizes activity against bacteria

• Differences highlighted between prokaryotic and eukaryotic cells influence drug targeting

• Table 10.1 outlines Mechanisms of Antimicrobial Action (summary below)

Mechanisms of Antimicrobial Action

• Inhibition of cell wall synthesis

• Inhibition of protein synthesis (translation, ribosomes)

• Disruption or alteration of the cytoplasmic membrane

• Inhibition of general metabolic pathways

• Inhibition of DNA or RNA synthesis

• Inhibition of pathogen attachment to or recognition of host

• Figure references: Figure 10.3a/c/d illustrate cell wall synthesis inhibitors and beta-lactam drugs

Inhibition of Cell Wall Synthesis

• Goal: prevent bacteria from increasing peptidoglycan; existing peptidoglycan remains

• Effective only for growing cells; bacteria with weakened walls lyse

• Beta-lactams are prominent in this group

  • Functional groups: beta-lactam rings

  • Mechanism: bind to enzymes that cross-link NAM subunits

• Semisynthetic derivatives of beta-lactams

  • More stable in acidic environments

  • More readily absorbed

  • Less susceptible to deactivation

  • More active against a broader range of bacteria

• Simplest beta-lactams: effective mainly against aerobic Gram-positive bacteria

• Vancomycin and cycloserine – Interfere with peptide bridges linking NAM subunits (e.g., alanine-alanine bridges) in many Gram-positives

• Bacitracin – Blocks secretion of NAG and NAM from the cytoplasm

• Isoniazid and ethambutol – Disrupt mycolic acid formation in mycobacterial species; require prolonged administration (months to years) to be effective

• Figure 10.3d: Penicillin effect on NAM-NAM cross-links

• Structural formulas of some beta-lactam drugs depicted in Figure 10.3c

• Alterations to make synthetic derivatives (summary): improved stability, absorption, spectrum, and activity

Inhibition of Cytoplasmic Membranes

• Some drugs form channels through cytoplasmic membranes and disrupt integrity

• Amphotericin B – Binds ergosterol in fungal membranes

  • Humans are somewhat susceptible due to cholesterol similarity to ergosterol

  • Bacteria lack sterols; not susceptible to amphotericin B

• Antifungal drugs targeting ergosterol synthesis

  • Azoles (e.g., fluconazole)

  • Allylamines (e.g., terbinafine)

• Some drugs disrupt membrane transport

  • Pyrazinamide – used against M. tuberculosis

• Some antiparasitic drugs alter permeability of membranes in parasitic worms

• Remember! Proteins are required for structure, regulation, enzymes in metabolism, and membrane transport

  • Prokaryotic ribosomes are 70 ext{S} (composed of 30 ext{S} and 50 ext{S} subunits)

  • Eukaryotic ribosomes are 80 ext{S} (composed of 40 ext{S} and 60 ext{S} subunits)

  • Drugs can selectively target translation; mitochondria in animals contain 70S ribosomes

Inhibition of Protein Synthesis

• Drugs can selectively target bacterial translation without harming host ribosomes

• Aminoglycosides (e.g., streptomycin, gentamicin)

  • Bind to the 30S subunit and cause misreading of mRNA

• Tetracyclines

  • Bind to the A site on the ribosome and block tRNA docking, preventing amino acid addition

• Some drugs interfere with the 50S subunit

  • Chloramphenicol – Blocks the enzymatic site of the 50S subunit, hindering peptide bond formation

• Lincosamides, streptogramins, and macrolides

  • Bind to a different portion of the 50S subunit; prevent movement of the ribosome; translation halts

• Mupirocin – Inhibits isoleucyl-tRNA synthetase (isoleucine incorporation is blocked)

• Antisense nucleic acids (fomiversen)

  • RNA or single-stranded DNA complementary to pathogen mRNA; blocks ribosomal subunit attachment; no human mRNA effect

• Oxazolidinones

  • Block initiation of translation; used as a last resort for some Gram-positive resistant bacteria (MRSA, VRSA)

• Figure 10.4 illustrates multiple sites of protein synthesis inhibition

Inhibition of Metabolic Pathways

• Antimetabolic agents effective when pathogen and host metabolic processes differ

• Atovaquone – Interferes with electron transport in protozoa and fungi

• Quinolones – Interfere with parasite metabolism (e.g., malaria)

• Heavy metals (e.g., arsenic, mercury) – Inactivate enzymes

• Agents disrupting tubulin polymerization and glucose uptake in protozoa and parasitic worms

• Drugs that block viral activation or replication processes

• Metabolic antagonists (e.g., sulfonamides)

• Sulfonamides – Structural analogs of PABA, which is crucial for nucleotide synthesis

• Some drugs bind to enzymes involved in converting dihydrofolic acid to tetrahydrofolate (THF); examples include Trimethoprim

• Antiviral agents targeting viral metabolism – Amantadine, rimantadine (uncoating inhibitors); protease inhibitors interfere with HIV replication

• Figure 10.6 provides an overview of antimetabolic action of sulfonamides

Inhibition of Nucleic Acid Synthesis

• Several drugs block DNA replication or mRNA transcription

• Effects can occur in both eukaryotic and prokaryotic cells; not normally used to treat infections in humans

• Nucleotide or nucleoside analogs

  • Interfere with function of nucleic acids; distort shapes; block replication, transcription, or translation

  • Most often used against viruses; also relevant for rapidly dividing cancer cells

• Quinolones and fluoroquinolones

  • Inhibit bacterial DNA gyrase (topoisomerase II)

• Inhibitors of RNA polymerase during transcription

• Reverse transcriptase inhibitors

  • Target HIV replication; humans lack reverse transcriptase; selective toxicity

• Figure 10.7 shows nucleotides and antimicrobial analogs

Prevention of Virus Attachment

• Attachment antagonists block viral attachment or receptor proteins

• Blocked by peptide and sugar analogs of attachment or receptor proteins

• Blocked viruses cannot attach or enter host cells

• New area of antimicrobial drug development

• Arildone and pleconaril – Antagonists of poliovirus/certain cold virus receptors

  • They block attachment and deter infections

Clinical Considerations in Prescribing Antimicrobial Drugs

• Ideal Antimicrobial Agent characteristics

  • Readily available; inexpensive

  • Chemically stable; easily administered

  • Nontoxic and nonallergenic; selectively toxic against a wide range of pathogens

• Spectrum of Action

  • Narrow-spectrum – effective against few organisms

  • Broad-spectrum – effective against many organisms

  • Broad spectrum may allow secondary or superinfections due to disruption of normal flora

• Consider the Effectiveness of therapy

  • Diffusion susceptibility test (Kirby-Bauer)

  • Minimum inhibitory concentration (MIC) test

  • Minimum bactericidal concentration (MBC) test

• Figures 10.9–10.11 illustrate diffusion, MIC, and E-test concepts

Routes of Administration

• Topical: for external infections

• Oral: no needles; self-administered

• Intramuscular: drug delivered into muscle

• Intravenous: directly into bloodstream

• Distribution to infected tissues depends on the route; Figure 10.13 shows blood level implications

Safety and Side Effects

• Disruption of normal microbiota can lead to secondary infections and superinfections

• Greatest concern in hospitalized patients

• Toxicity concerns: kidneys, liver, nerves; requires careful prescribing, especially during pregnancy

• Allergies: rare but potentially life-threatening (anaphylactic shock)

• Figure 10.14 summarizes side effects related to toxicity

Antimicrobial Drug Resistance

• Some pathogens are naturally resistant

• Resistance can be acquired via two main mechanisms

  • Mutations in chromosomal genes

  • Acquisition of resistance plasmids (R-plasmids) via transformation, transduction, and conjugation

• Figure 10.15: overview of resistant strain development

MRSA

• Methicillin-resistant Staphylococcus aureus

• Timeline of resistance development:

  • 1950s: Penicillin resistance

  • 1980s: Methicillin resistance

  • 1990s: Vancomycin resistance reported

• Variants: VISA (Vancomycin-intermediate-resistant) and VRSA (Vancomycin-resistant)

Mechanisms of Resistance

• Bacterial strategies to evade drugs

  • Produce enzymes that destroy or deactivate drugs (e.g., beta-lactamases)

  • Slow or prevent drug entry into the cell

  • Alter drug target so binding is less effective

  • Alter metabolic chemistry to bypass the drug action

  • Pump drugs out of the cell (efflux)

  • Biofilms retard drug diffusion and slow metabolic rate

  • Mycobacterium tuberculosis can produce MfpA protein to reduce drug binding

• Figure 10.16 illustrates beta-lactamase-mediated penicillin inactivation

Multiple Resistance and Cross-Resistance

• Pathogens can acquire resistance to multiple drugs

• Common when R-plasmids are exchanged

• Frequent in hospitals and nursing homes due to high drug usage

• Superbugs: organisms with multiple resistance traits

• Cross-resistance: resistance to multiple drugs with related mechanisms

Retarding Resistance

• Strategies to slow resistance development

  • Maintain high drug concentrations for sufficient time to kill sensitive cells and inhibit others

  • Combination therapy to exploit synergism (not antagonism)

  • Develop new drug variations: second-generation, third-generation drugs

  • Search for new antibiotics, semisynthetics, synthetics

  • Explore bacteriocins and design drugs complementary to microbial proteins to inhibit them

• Figure 10.17 demonstrates an example of synergism between two antimicrobial agents