PMP201 - Antibiotics Class & Mechanisms Part 3

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Questions and Answers

Qual class de antibioticos bloquea le translocation?

Tetracyclines

Aminoglycosides

Clindamycin (correct)

Oxazolidinones

Qual antibiotico ha un suffis de '-cycline' e bloquea le attachment de tRNA a site A in le ribosome?

Chloramphenicol

Aminoglycosides

Sulphonamides

Tetracyclines (correct)

Qual enzyma es inhibited per sulphonamides durante le synthesis de acido folico?

Dihydropteroate synthase (DHPS) (correct)

Dihydrofolate reductase (DHFR)

Folate transporter

PABA synthase

Qual substance es targete da trimethoprim e ha un alta affinitate pro le enzyme bacterial?

Dihydrofolate reductase Signup and view all the answers

Quale class de antibioticos agisce como antimetabolites e ha un effect bacteriostatic?

Sulphonamides Signup and view all the answers

Perque le bacterias non pote uptake acido folico de foris?

Bacterias sintetisa acido folicoเอง Signup and view all the answers

Qual class de antibioticos causa mRNA misreading durante le translation?

Aminoglycosides Signup and view all the answers

Quale de le sequenti marcatores es usate pro le diagnosi microbiologic de mycobacteria?

St_annotation acida Signup and view all the answers

Quale combination de medicamentos es parte del regime terapeutico initial pro tuberculose?

Rifampicina, Isoniazida, Pyrazinamida, Ethambutol Signup and view all the answers

Quale es un caractere distinctive del muros celular de mycobacteria?

Rico in acidos mycolicos Signup and view all the answers

Quale explica le resistentia del mycobacteria a antibioticos?

Muralla celular robuste e hydrophobe Signup and view all the answers

Quale es un tipo de tuberculose resistente a medicamentos?

Multidrug-resistant TB (MDR-TB) Signup and view all the answers

Qual es le mechanism de action de metronidazole?

Generar radicales libere in bacteria Signup and view all the answers

Qual es le principale efecto secundario de rifampicin?

Discoloration de fluidos corporale Signup and view all the answers

Qual es le principal contraindication pro l'uso de rifampicin?

Porfirias acute Signup and view all the answers

Qual microbio es specificemente targetate per metronidazole?

Protozoos e anaerobes Signup and view all the answers

Que genera le metronidazole quando es reduce in cellulas?

Radicales nitroso instables Signup and view all the answers

Qual es le importancia del potencial redox in le mechanism de metronidazole?

Permititir le reduction de metronidazole Signup and view all the answers

Qual interaction es relevante pro rifampicin?

Inducter le cytochrome P450 Signup and view all the answers

Quo resulta de le interaction de radicales libere (ROS) con le DNA?

Fragmentation del DNA Signup and view all the answers

Qual non es un efecto secundario de metronidazole?

Resistencia croissante Signup and view all the answers

Qual es le spectre de action de metronidazole?

Bacterias anaerobes e protozoos Signup and view all the answers

Qual es le principale mechanismus de action de sulfonamidas e trimethoprim?

Blocking de la sintese de acido folico Signup and view all the answers

Qual es un uso typic de co-trimoxazole?

Infection de tracto urinar Signup and view all the answers

Qual es un side effect significative de co-trimoxazole?

Deficientia de folato Signup and view all the answers

Qual es le mechanismus de action del fluoroquinolones?

Targeting de topoisomerases Signup and view all the answers

Qual es le consequence de le uso de co-trimoxazole durante le prime trimester de gravidanza?

Formation de defectos de tubo neural Signup and view all the answers

Qual es le effecto de rifampycin super le sintetisation de acidos nucleicos?

Inhibition de la transcription de RNA Signup and view all the answers

In le contextu de co-trimoxazole, qui debe evitar le medicamento?

Pazientes con discrasia sanguinee Signup and view all the answers

Qual es le principal causa de hyperkalaemia relacionada al uso de co-trimoxazole?

Alteration de renal function Signup and view all the answers

Qual es un importante caution pro l'uso de co-trimoxazole in neonatos?

Predisposition a deficientia de folato Signup and view all the answers

Qual tipo de enzima bacteriana es inhibit per fluoroquinolones?

Gyrase de ADN Signup and view all the answers

Qual es un effecte secundario notabile asociato con fluoroquinolones?

Seizures Signup and view all the answers

Qual grupo de bacterias es fluoroquinolones effective contra?

Gram + e Gram - Signup and view all the answers

Qual fluoroquinolone es typicamente usate pro infectiones de tracto urinar?

Ciprofloxacin Signup and view all the answers

Qual es le mechano de action de rifampicina?

Inhibition de la RNA polymerase Signup and view all the answers

Qual est un contraindicatio pro fluoroquinolones?

Storia de dano de tendon Signup and view all the answers

Qual es un effecte raro de fluoroquinolones?

Prolongation del intervalo QT Signup and view all the answers

Qual es le consequence del uso excessivo de fluoroquinolones?

Desarrollo de resistencia Signup and view all the answers

Qual es un uso comun de rifampicina?

Tuberculosis Signup and view all the answers

Qual fluoroquinolone es asociato con tendon rupture?

Levofloxacin Signup and view all the answers

Study Notes

PMP201 - Infection ISU: Antibiotics - Drug Classes and Mechanisms - Part 3

Course: Infection Immunology
Date: 6th November 2024
Lecturer: Dr. Giulio Nannetti
Topic: Antibiotics - Drug Classes and Mechanisms - Part 3

Previous & Complementary Knowledge

Health, Disease, and Patient (PMP101): 2023/24
Microbiology Lectures: Bacteria composition
Bacterial Growth
Patient-Centred Learning I (PMP201): 2024/25
Antibiotics Overview 1: Dr. Guirguis
Antibiotics Overview 2 & 3: Dr. Guirguis
Antibiotic Chemistry: Dr. Padalino

Learning Outcomes

Outline antibacterial mechanism, effect, and properties of the main types of antimetabolite antibiotics
Outline antibacterial mechanism, effect, and properties of inhibitors of nucleic acids synthesis
Outline antibacterial mechanism, effect, and properties of antibiotics acting with an alternative mechanism of action
Identify therapeutic agents for tuberculosis

Mechanisms of Action - RECAP

1. Inhibition of cell wall synthesis:
- Beta-lactams (penicillins, cephalosporins, monobactams, carbapenems)
- Glycopeptides (vancomycin)
4. Inhibition of nucleic acids synthesis:
- Fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin)
- Rifamycins (rifampin)
2. Inhibition of protein synthesis:
- Aminoglycosides
- Tetracyclines
- Macrolides
- Lincosamides
- Chloramphenicol
- Oxazolidinones
3. Acting as antimetabolites:
- Sulfonamides
- Trimethoprim
- Mycolic acid synthesis inhibitors (isoniazid)

1- Inhibitors of Cell Wall Synthesis - RECAP

Cell wall inhibitors:
- β-lactams, penicillins, cephalosporins, monobactams
- Carbapenems
- Glycopeptides
- Vancomycin

β-Lactam and Non β-Lactam Classes Inhibiting Cell Wall Synthesis - RECAP

β-lactams (bactericidal):
- Target transpeptidase enzymes (mimicking their substrate).
- Structurally diverse chemical classes (with a β-lactam ring)
- Penicillins
- Cephalosporins
- Carbapenems
- Monobactams
Non β-lactams (Glycopeptide): (Vancomycin) (bactericidal)
- No β-lactam ring
- Target transpeptidase's substrate
- Shared mechanism of action

Patient Centred Integration

Human Biology
Clinical Pharmacy
Cellular & Molecular Bioscience
Pharmacology & Therapeutics
Pharmaceutical Chemistry
Pharmacy Practice
Pharmaceutics

3) Antibiotic Classes Acting as Antimetabolites

Inhibit bacterial metabolic pathways (eukaryotic cells have different pathways)
Selective toxicity
Target key enzymatic steps in folic acid synthesis (essential for nucleotide production)
Bacteriostatic effect

3a) Sulphonamides (Sulfamethoxazole)

Mechanism:
- Folic acid is key for producing purines (nucleotides)
- Bacteria cannot absorb folic acid externally
- Bacteria synthesize folic acid starting from PABA
- Sulphonamides compete with PABA for the first enzyme: DHPS
In human bodies: Folic acid (Vitamin B9) obtained through the diet

3b) Trimethoprim

Mechanism:
- DHFR (dihydrofolate reductase) targeted
- Present in human cells (for folic acid activation)
- 100,000x greater affinity for bacterial DHFR over human counterpart

3a+b) Sulphonamides + Trimethoprim

Sequential blocking mechanism: Both block folic acid synthesis at various steps.
Synergistic effect: Combined action potentiates antibacterial effect
Bacteriostatic effect: Inhibits bacterial growth.
Spectrum: Broad-spectrum (Gram-positive & Gram-negative)

3a+b) Sulphonamides + Trimethoprim (Co-trimoxazole) - Side Effects & Cautions

Side effects:
- Folic Acid Deficiency (esp. pregnant women)
- Hyperkalaemia (high potassium, renal monitoring)
- Hypersensitivity; rash and anaphylaxis
Contraindications:
- First trimester of pregnancy
- Patients with blood dyscrasias (e.g., decreased blood cell counts)
- Acute porphyria
- Elderly and neonates
- Increased risk of folate deficiency

4) Inhibition of Nucleic Acids Synthesis

Inhibitors of DNA synthesis:
- Fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin)
Inhibitors of RNA synthesis:
- Rifamycins (rifampin)

4) Nucleic Acid Synthesis Inhibition

Fluoroquinolones: Target DNA topoisomerases, crucial for replication
Rifamycins: Inhibit RNA polymerase, disrupting mRNA transcription.
Bactericidal effect
Lower selective toxicity due to similarities in bacterial and eukaryotic processes.

4a) Fluoroquinolones

Mechanism:
- Inhibit bacterial topoisomerases (DNA replication disruption).
- DNA gyrase inhibition in Gram-negative bacteria.
- Topoisomerase IV inhibition in some Gram-positive bacteria (at higher doses)
Spectrum:
- Broad-spectrum (including H. influenzae, P. aeruginosa).
Uses:
- Serious RTIs (CAP), skin/soft tissue infections, UTIs
Side effects:
- GI distress
- Tendonitis/rupture (-2%)
- Muscle weakness/joint pain
- QT prolongation (rare)/aortic aneurysm (very rare)
- Seizures (rare) /peripheral neuropathy
Cautions / Contraindications:
- History of tendon damage
- Corticosteroid use
- QT prolongation risk factors
- Epilepsy, psychiatric disorders
- Renal impairment
- Exposure to sunlight

4b) Rifamycins (Rifampicin)

Mechanism:
- Inhibit bacterial mRNA synthesis by blocking the bacterial RNA polymerase.
Bactericidal effect
Uses:
- Tuberculosis, meningitis (N. meningitidis/H. influenzae), related infections
Side effects:
- GI distress
- Minor hepatotoxicity
- Body fluid discoloration (urine/sweat turns orange - harmless)
- Many drug interactions (cytochrome P450 inducer)
Contraindications:
- Patients with acute porphyrias

5) Alternative Mechanisms

Nitroimidazoles: (Metronidazole, Nitrofurantoin)
- Generate reactive free radicals, disrupting DNA and other bacterial components
- Bactericidal effect
- Spectrum: Mainly against anaerobic bacteria & some Gram-positives(e.g., E. coli)
Uses:
- Treating anaerobic bacterial infections, H. pylori eradication; UTIs (Nitrofurantoin is a significant component).

5a) Nitroimidazoles (Metronidazole)

Mechanism: Generating free radicals in anaerobic bacteria.
Spectrum: Only anaerobes (including protozoa). Requires low redox potential. Aerobic bacteria have high redox potential.
Uses: Treating anaerobic infections, H. pylori eradication.

5b) Nitrofurantoin

Mechanism: Generates reactive free radicals, interfering with RNA, DNA, and protein synthesis.
Spectrum: Effective against most Gram-positive & some Gram-negative bacteria (E. coli)
Uses: Treating and preventing uncomplicated acute UTIs.

Treatment for Tuberculosis (TB)

10.6 million new TB cases and 1.6 million deaths due to TB reported in 2021 globally.
TB caused by Mycobacterium tuberculosis organisms.
Infection can be pulmonary (lungs) or extrapulmonary (other organs).
TB can occur in latent (asyptomatic) or active (symptomatic) forms.
Microbiologically diagnosed using acid-fast staining (lipid-rich cell wall) or auramine fluorescent staining (mycolic acid).

Mycobacterium tuberculosis

Gram-positive and aerobic (oxygen requirement)
Complex and unique cell wall: Thick, hydrophobic, waxy (lipids) – preventing antibiotics entry
Virulence factors: Survive and replicate within macrophages.
Therapeutic target: Cell wall components (e.g., mycolic acids, arabinogalactan).

Cell Wall of Mycobacteria

Unique components: Glycolipids (TDM, GPL, PDIM), mycolic acids, arabinogalactan, peptidoglycan
Thick, hydrophobic barrier: Impedes antibiotic penetration.
The nature of the cell wall renders mycobacterium highly resistant to traditional antibiotics

Treatment for Tuberculosis (TB) - First-Line Drugs (RIPE)

Rifampicin (RNA polymerase inhibitor)
Isoniazid (inhibitor of mycolic acid synthesis)
Pyrazinamide (interferes with fatty acid synthesis)
Ethambutol (interferes with the synthesis of arabinogalactans)

Treatment for Tuberculosis (TB) - Drug Resistance

Newly diagnosed TB: RIPE (6 months) and subsequent continuation (RI), 4 additional months.
Re-treatment of TB: RIPE and streptomycin (2 months) & a continuation with ethambutol (5 months)
Drug-Resistant TB (MDR-TB, XDR-TB): Rifampicin and Isoniazid resistance, and other second-line drug resistances. Treatment is tailored for resistance; Supervision is emphasized to meet patient compliance.

Quizzes

Trimethoprim Target: Folic acid synthesis
Not a First Line TB Drug: Amoxicillin

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Description

Este quiz explora le classes de antibioticos e lor mecanismos de action in detail. In particular, us considerara le antimetabolitos e inibitores del synthesis de acidos nucleicos. Se preparara pro examinar le therapias pro tuberculose e alios aspectos critical del immunologia de inflection.