Antibiotics and Antibiotic Resistance

Learning Outcomes

• Understand the mechanisms of action of antibiotics.

• Determine appropriate antibiotic use based on infection and microbial characteristics.

• Explain resistance mechanisms and their relationship to specific antibiotics.

• Discuss challenges in developing antiviral, antifungal, and new antibiotic drugs.

• Describe virulence factors of Staphylococcus aureus and factors influencing its pathogenicity.

Introduction to Antimicrobials

Definition and Importance

• Antimicrobials are agents that kill or inhibit the growth of microorganisms, including bacteria, viruses, fungi, and parasites.

• They are essential for treating infectious diseases and preventing the spread of pathogens.

• Antimicrobials include antibiotics (bacteria), antivirals (viruses), antifungals (fungi), and antiparasitics (parasites).

• Example: Penicillin inhibiting bacterial growth on an agar plate.

Features of Good Antimicrobial Drugs

Desirable Properties and Targets

• Selective toxicity: Targets microbial processes without harming host cells.

• Broad or narrow spectrum: Effective against a wide range or specific types of microbes.

• Low potential for resistance development.

• Targets essential microbial structures or functions (e.g., cell wall, protein synthesis).

Consequences of Antibiotic Use

Impact on Microbiota and Resistance

• Normal microbiota suppresses opportunistic pathogens.

• Broad-spectrum antibiotics can kill beneficial microbes, allowing drug-resistant pathogens to proliferate and cause superinfections.

• Superinfection: Secondary infection by resistant organisms after antibiotic treatment.

Antibiotic Administration

Routes and Pharmacokinetics

• Common routes: Oral, intramuscular (IM), intravenous (IV).

• Pharmacokinetics: Drug concentration in plasma varies by route and time ( to ).

• IV administration leads to rapid peak concentration; oral/IM routes have slower absorption.

Societal Factors in Antibiotic Use

Patient Pressure and Public Perceptions

• Patients often pressure physicians for antibiotics, even when not indicated.

• Misconceptions exist about antibiotics treating viral infections.

*Additional info: Table summarizes GP perceptions of patient pressure for antibiotics.*

*Additional info: Table shows public and parental misconceptions about antibiotic effectiveness.*

Spectrum of Antimicrobials

Range of Activity

• Broad-spectrum antibiotics act against a wide variety of organisms (e.g., tetracyclines).

• Narrow-spectrum antibiotics target specific groups (e.g., penicillin for Gram-positive bacteria).

• Antimicrobials can target bacteria, fungi, viruses, and obligate parasites.

Potential Targets of Antimicrobials

Cellular Structures and Processes

• Cell wall synthesis (e.g., beta-lactams, vancomycin)

• Protein synthesis (e.g., tetracyclines, macrolides)

• DNA gyrase (e.g., quinolones)

• RNA polymerase (e.g., rifampin)

• Metabolic pathways (e.g., sulfa drugs)

• Cytoplasmic membrane structure/function

Cell Wall Synthesis Inhibitors

Beta-lactams

• Most common class of antibiotics (e.g., penicillins, cephalosporins).

• Inhibit cell wall synthesis by interfering with transpeptidation (cross-linking of peptidoglycan).

• Structure: Beta-lactam ring essential for activity.

Mechanism of Action

• Bind to penicillin-binding proteins (PBPs).

• Prevent cross-linking of peptidoglycan, leading to cell lysis.

Cephalosporins

• Similar mechanism to beta-lactams.

• Increased resistance to beta-lactamases.

• Example: Ceftriaxone.

Non-beta-lactam Cell Wall Inhibitors

• Include vancomycin, bacitracin, daptomycin.

• Target different steps in peptidoglycan synthesis or membrane integrity.

Growth Factor Analogs

Mechanism and Examples

• Structurally similar to essential growth factors but disrupt normal cell metabolism.

• Sulfa drugs mimic para-aminobenzoic acid (PABA) and inhibit folic acid synthesis.

• Trimethoprim inhibits a later step in folic acid synthesis.

• Resistance: Bacteria may acquire ability to uptake folic acid from environment.

• Combination therapy (sulfa drug + trimethoprim) increases efficacy and reduces resistance.

Antibiotics Targeting Protein Synthesis

Major Classes and Mechanisms

• Target bacterial ribosomes (30S or 50S subunits), inhibiting translation.

• Chloramphenicol, macrolides, lincosamides: Bind 50S subunit, inhibit peptide bond formation.

• Aminoglycosides: Bind 30S subunit, cause misreading of mRNA.

• Tetracyclines: Bind 30S subunit, block tRNA attachment.

Antibiotics Targeting DNA Gyrase

Quinolones

• Disrupt DNA gyrase, an enzyme essential for DNA replication and supercoiling.

• Examples: Ciprofloxacin, moxifloxacin.

• Inhibition leads to DNA damage and cell death.

Antibiotics Targeting Nucleic Acid Synthesis

RNA Synthesis Inhibitors

• Rifampin: Binds bacterial RNA polymerase, blocks transcription.

• Actinomycin: Binds DNA, interferes with RNA polymerase elongation.

• Bacterial and eukaryotic RNA polymerases are structurally similar, but eukaryotic enzymes are more complex.

Antibiotic Resistance

Selection and Genetic Basis

• Antibiotic use selects for pre-existing resistant strains; does not create resistance de novo.

• Resistance genes are often carried on plasmids or mobile genetic elements, facilitating horizontal gene transfer.

Mechanisms of Resistance

• Efflux pumps: Remove antibiotic from cell (e.g., tetracyclines, macrolides).

• Blocked penetration: Prevent antibiotic entry (e.g., penicillins, cephalosporins).

• Inactivation of enzymes: Destroy or modify antibiotic (e.g., beta-lactamases).

• Target modification: Alter antibiotic target (e.g., ribosomal mutations).

*Additional info: Other mechanisms include target overproduction, target mimicry, and enzymatic bypass.*

Antiviral Drugs

Challenges and Targets

• Difficult to achieve selective toxicity due to reliance on host cell machinery.

• Targets include viral entry/fusion, nucleic acid synthesis, protease activity, and specific viral enzymes.

• Example: Tamiflu (neuraminidase inhibitor) blocks release of influenza virus from host cells.

Antifungal Drugs

Challenges in Treatment

• Fungal infections are increasingly common in immunocompromised individuals.

• Fungi are eukaryotes, sharing many cellular features with humans, making selective toxicity difficult.

• Common targets: Ergosterol synthesis (unique to fungi), cell wall synthesis.

Staphylococcus aureus and Antibiotic Resistance

Virulence and Resistance Trends

• Staphylococcus aureus is a major pathogen with multiple virulence factors.

• Development of resistance (e.g., MRSA, VISA, VRSA) has increased over time, complicating treatment.

• Virulence factors include toxins, enzymes, and surface proteins that aid in colonization and immune evasion.

Discovery and Development of New Antimicrobials

Challenges and Strategies

• Only ~1% of isolated antibiotics are clinically useful due to toxicity, poor pharmacokinetics, or resistance.

• FDA approvals for new antimicrobials have declined in recent decades.

Methods for Developing New Antimicrobials

• Computer modeling and structural biology (e.g., saquinavir for HIV).

• Screening for antibiotic activity from uncultured bacteria and new environments (e.g., platensimycin).

• Combination therapy to enhance efficacy and reduce resistance (e.g., beta-lactam + beta-lactamase inhibitor, ART/HAART for HIV, sulfa drugs + trimethoprim).