Antibiotics
Content:
1. Antibiotics classification
2. Mechanism of action antibiotics
3. Cell wall synthesis inhibitors
4. Cell membrane integrity disruptors ------------Part 1
5. Nucleic acid synthesis inhibitors
6. Protein synthesis inhibitors
7. Metabolic pathway inhibitors
8. Reference
2. Mechanism of action antibiotics
3. Cell wall synthesis inhibitors
4. Cell membrane integrity disruptors ------------Part 1
5. Nucleic acid synthesis inhibitors
6. Protein synthesis inhibitors
7. Metabolic pathway inhibitors
8. Reference
1. Antibiotics classification
broadly defined as chemical agents that kill or inhibit the growth of microorganisms
classified as
- broad-spectrum: act against wide range of microorganisms
- narrow-spectrum: act against very few types of microorganisms
- bactericidal: kill bacteria
- bacteriostatic: only stop bacteria from growing
Selection of antibiotic
- depends largely on
- clinical manifestation of the infection
- the patient profile
- often guided by
- Kirby-Bauer method: culture sensitivity
- dilution test: determine the lowest concentration of antibiotic that inhibits visible bacterial growth known as minimum inhibitory concentration (MIC)
- the lowest concentration of antibiotic that kills at least 99.9% of bacteria known as the minimum bactericidal concentration (MBC)
2. Mechanism of action antibiotics
Five categories
- Cell wall synthesis inhibitors
- Cell membrane integrity disruptors
- Nucleic acid synthesis inhibitors
- Protein synthesis inhibitors
- Metabolic pathway inhibitors
3. Cell wall synthesis inhibitors
Cell wall is essential for the growth and survival of bacteria
- maintain bacterial cell shape
- protects it against spontaneous cell lysis
- due to the high internal osmotic pressure that results from high concentration of proteins within the bacterial cytoplasm
Two different types of cell wall
Gram-negative:
- composed of the outer membrane
- linked by lipoproteins to a thin inner layer of peptidoglycan
Gram-positive:
- composed of many interconnected layers of peptidoglycan
- it lacks the outer membrane
Peptidoglycan gives both cell wall types rigid and protective qualities
- consists of glycan chains of alternating n-acetylglucosamine (NAG)& n-acetylmuramic acid (NAM) with short peptide chain attached to it
Biosynthesis of peptidoglycan
- mediated by transpeptidase enzymes
- also known as penicillin-binding proteins
- penicillin-binding proteins catalyze the final transpeptidation reaction
- results in formation of bond between the last lysine residue of one peptidoglycan and the terminal alanine on the other strand
- in order for bacteria to grow and divide a new cell wall, must be continuously built this way
a. Beta-lactam antibiotics
- inhibitors of cell wall synthesis
- characterized by beta-lactam ring at the core of structure
- resembles substrates for penicillin-binding protein
- when penicillin-binding protein binds to beta-lactam ring portion of the drug
- covalent bond is formed
- resulting in permanently blocked active site
- makes the enzyme unable to perform their role in cell wall synthesis
- leads to death of bacteria due to osmotic instability or autolysis
Drug:
- penicillins
- cephalosporins
- carbapenems
- monobactams
can easily kill all harmful bacteria
But, over the years exposure to antibiotics provided bacteria with selective pressures which led to emergence of different resistance mechanisms
most common mechanism: bacterial synthesis of beta-lactamases
- beta-lactamases
- enzymes produced by certain types of bacteria
- break the beta-lactam ring
- destroy antibacterial activity
- Treat: the use of beta-lactamase inhibitors in combination with beta-lactam antibiotics
- beta-lactamase inhibitors irreversibly bind to and inhibit beta-lactamase enzymes
- Two exceptions: carbapenems & monobactams
- don't need to be combined with beta-lactamase inhibitors
- because they have modified beta-lactam rings in their structures
- provide them with significant resistance to beta-lactamases
【Pharmacology】Pharmacology Hack 12. Penicillin (PCN)
Beta-lactamase inhibitors:
- avibactam
- clavulanic acid
- sulbactam
- tazobactam
Side-effects
- nausea
- vomiting
- diarrhea
- allergic reactions ranging from mild rashes to life-threatening anaphylaxis
Enzymatic steps involved in cell wall synthesis
- cytoplasmic enzyme enolpyruvate transferase (MurA)
- MurA catalyzes the addition of phosphoenolpyruvate (PEP) to UDP-n-acetyl-glucosamine
- to form UDP-n-acetyl-muramic acid to
- three amino acids are sequentially added
- next crucial step involves two enzymes
- d-alanine racemase --- converts l-alanine into d-alanine
- d-alanine:d-alanine ligase --- joins to d-alanine molecules which are then incorporated into the growing peptidoglycan precursor
- With the help of translocase enzyme,
- peptidoglycan precursor is transferred to the lipid carrier called undecaprenyl-pyrophosphate
- also known as bactoprenol
- followed by sequential addition of n-acetylglucosamine along with five amino acid molecules
- Once this cell wall building block is transported across the inner membrane,
- penicillin-binding proteins catalyze the final step of polymerization of n-acetylmuramic acid and n-acetylglucosamine complexes via transglycosylation and cross-linking of chains via transpeptidation
- bactoprenol lipid carrier gets dephosphorylated
- enables it to perform another round of transfer
b. Fosfomycin
- acts in the first cytoplasmic step of the cell wall synthesis by
- irreversibly inhibiting MurA enzyme
- prevents the formation of peptidoglycan precursor
- leads to bacterial cell death
Side effects
- nausea
- dizziness
- headache
- diarrhea
c. Cycloserine
- because of its chemical resemblance to d-alanine cycloserine
- competitively inhibits both d-alanine racemase and d-alanine:d-alanine ligase
- when both of these enzymes are inhibited
- d-alanine residues cannot be formed
- previously formed d-alanine molecules cannot be joined together again
- the formation of peptidoglycan precursor is disrupted
- leads to death of bacteria
Side effects
- neurologic and psychiatric disturbances such as
- peripheral neuropathy
- depression
- psychosis
d. Vancomycin
- belongs to a small family of antibiotics called glycopeptides
- works in the late stages of cell wall synthesis
- vancomycin interferes with both transpeptidation and transglycosylation
- during peptidoglycan assembly by binding to two d-alanine residues at the top of the peptide chains
- this binding prevents linking of long polymers of n-acetylmuramic acid and n-acetylglucosamine that form the peptidoglycan backbone
- prevents cross-linking between amino acid residues in the peptidoglycan chain
- this brings cell construction to a halt
- results in bacterial cell death
Side effects
- When administered intravenously
- hypotension along with flushing of the upper body condition
- known as redman syndrome
- In rare instances, may cause
- nephrotoxicity
- ototoxicity
- blood disorders including neutropenia
e. Bacitracin
- works by binding to bactoprenol
- inserts the peptidoglycan into the growing cell wall
- prevents the dephosphorylation of the transport protein
- unable to regenerate and perform its job in construction of the cell wall
Side effects
- when used topically
- rarely causes side-effects, other than minor skin irritation
- when administered intravenously
- nausea
- vomiting
- allergic reactions
- nephrotoxicity
Mycobacteria
- highly pathogenic organisms
- responsible for deadly diseases such as
- tuberculosis
- leprosy
- notorious for their ability to resist most antibiotics
- toughness---exceptionally impermeable cell wall
- mycobacterial cell wall is made up five major components
- linked together the inner plasma membrane thin layer of peptidoglycan and arabinogalactan surrounded by a thick layer of mycolic acid with a lipid containing outer membrane
- cell wall is essential to the survival of mycobacteria
Antituberculosis drugs
primarily target mycobacterial cell wall synthesis
Drug:
- Isoniazid
- prodrug which upon gaining entry into the cell
- must be first activated by bacterial catalase-peroxidase enzyme (KatG)
- once activated, in the presence of NADH,
- isoniazid forms adduct
- which then binds to and thereby inhibits the enoyl-acyl carrier protein reductase (InhA)
- InhA is a member of the type 2 fatty acid system
- which elongates long-chain fatty acids for the synthesis of mycolic acid
- Inhibition of mycolic acid synthesis
- leads to a loss of cell structural integrity and physiologic function
- results in bacterial cell death
- Ethambutol
- inhibition of membrane associate enzyme called arabinosyl transferase (EmbB)
- the enzyme that mediates polymerization of arabinose into arabinogalactan
- arabinogalactan: an essential component of the mycobacterial cell wall
- EmbB enzyme inhibition
- the cell wall permeability increases
- allowing toxic substances to enter the cell
Side effects
- isoniazid
- hepatotoxicity
- peripheral neuropathy
- ethambutol
- optic neuritis that can lead to vision loss
4. Cell membrane integrity disruptors
target primarily the cell membrane of bacteria
Drug:
- Daptomycin
- targets cytoplasmic membrane of gram-positive bacteria polymyxins
- works by forming a complex with calcium
- facilitates its insertion into the bacterial cell membrane
- daptomycin-calcium complexes aggregate within the membrane to form pore-like structures
- allow ions such as potassium to leak through
- causing depolarization of membrane potential
- eventually cell death
- Polymyxins
- small family of antibiotics
- target the outer membrane of gram-negative bacteria
- initially bind to the lipopolysaccharides in the outer membrane
- causing structural changes that increase membrane permeability allows polymyxins to enter in
- disrupt the inner cytoplasmic membrane
- leads to leakage of the cell contents
- eventually death of the bacteria
Side-effects
- Daptomycin: skeletal muscle toxicity
- Polymyxins: nephrotoxicity and neurotoxicity
8. Reference
https://youtu.be/mMk6VWVpRpo
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