Antibiotics 1 Flashcards
Cell Wall Synthesis Inhibitors I and II
What is the function of a bacterial cell wall?
Protects bacterial cells from the external environment.
Provides shape and rigidity to the cell.
What is the difference between gram-negative and gram-positive bacteria?
Different components.
Gram-negative: Thin cell wall found between inner and outer membrane.
Gram-positive: Thicker cell wall found on the outside of the cell membrane.
What is Peptidoglycan?
it is a polymer of peptide-linked chains of amino sugars.
a major component of most cell walls
Describe the structure of peptidoglycan.
The molecule consists of parallel polymers of disaccharides called glycan crosslinked with peptide chains of 4 amino acids
Long chains of peptidoglycan consist of repeating units of disaccharide made up of N-acetylglucosamine and N-Acetylmuramic acid.
n-acetylmuramic acid has a string of four amino acids which form cross-linking bridges with each other to create the rigidity and strength of the cell wall
The strength of bonds formed can vary between different bacteria
Describe the first phase of bacterial cell wall synthesis.
Begins inside the cell in cytoplasm with small peptidoglycan precursor molecules. Amino acids sequentially bind to N-acetyl muramic acid, usually finished with the addition of 2 alanine molecules attaching to form alanine terminus to form N acetylmuramyl (UDP) and N-glucosamine in the cytoplasm.
Describe the second phase of bacterial cell wall synthesis.
Precursor lipid intermediates synthesised. Lipid 1 complex forms when UDP molecule moves towards cytoplasmic membrane then binds to the membrane acceptor molecule (bactoprenol) via binding of one phosphate from the UDP and release of the UMP molecule.
N-acetylglucosamine transferred onto lipid complex releasing an intact UDP to form the lipid 2 complex.
What does the lipophilic bactoprenol molecule do next?
Aows transport of lipid 2 complex through the cytoplasmic membrane and extends the situated sites for incorporation, extending into the growing peptidoglycan wall.
Describe the final stage of bacterial cell wall synthesis.
Takes place on the outer side of cytoplasmic membrane involvng polymerisation of the newly sythesised dissacharide peptide unit.
This is incorporated into the growing cell wall via trans glycolstlation and transpeptidation reactions.
These reactions are cataysed by the penicilin binding poretins formt eh glycosidic and peptide bonds on the peptidoglycan cell wall.
What is the role of the transglucosylase enzyme in the 3rd phase of bacterial wall synthesis?
Binds together the N acetyl glucosamine of the incoming peptidoglycan precursor molecule and the end of the n-acetylmuramic acid of the growing peptidoglycan chain.
How does the cell wall become strong?
Cross-links formed between the peptides in the peptide chains by this enzyme.
Binds between the lysine of one chain and the penultimate alaine of a second chain causing the terminal alanine to be cleaved - a strong flexible mesh of peptidoglycan formed.
This is the basis of the gram-positive cell wall.
Describe the fate of bactoprenol after the 3rd phase of bacterial cell wall synthesis.
Recycled via loss of additional phosphate that was gained when N-acetylmuramic acid pentpeptide and is relocated inside the cytoplasmic membrane.
This makes it ready to transport further precursor molecules over the membrane.
Describe the purpose of antibiotics.
Inhibit bacterial cell wall synthesis causing bacterial growth inhibition and cell death.
Give some examples of B-lactam antibiotics
penicillin, cephalosporins and carbapenems
Describe the structure of B-lactam antibiotics
All have B lactam ring
Different penicillin made via modification of its sidechain
Complex cephalosporins have two modifiable side chains
Carbapenems have three modifiable side-chains
How was penicillin first produced?
By Mould Penicillium notum - name later changed to peicillium chrysogensum.
How was penicillin developed?
Penicillin found to produce 4 different types of penicillin - Pen G (in greatest quantity), K, F, and X
Penicillin preparations were isolated- found that some penicillin preparations were less effective at clearing some infections due to different strains, growth conditions and methods of purification caused by different types of penicillin present in different ratios.
Why was penicillin G more produced? What is the relevance of penicilin G?
Penicillin G is more active against Treponema pallidum (causative agent of syphilis, thus more effective to treat it)
Prompted synthesis of individual pure penicillin preparations to known F,G,F,K types for efficacy testing
Why were/are side chains of penicillins modified? What properties does this give modified penicillins?
Modifications to sidechains of each type gave different properties e.g different levels of hydrophobicity
and
Differing effectiveness against specific bacteria and relative toxicity to the host
List 4 limitations of penicillins.
Narrow spectrum of activity.
Hypersensitivity/allergy to penicillin- penicillin allergies are the most common cause of drug allergic reactions.
Sensitivity to gastric acid.
Kidneys rapidly remove it from mammalian systems.
How does a narrow spectrum of activity affect penicillin efficacy?
natural penicillin’s only had activity against a narrow range of organisms – ineffective against some of the most frequent causes of modern-day infection
What does an allergic reaction to penicillin look like?
rashes, swollen faces, can be as serious as anaphylactic shock.
side effects of penicillin can be mistaken for an allergic reaction.
How is penicillin’s sensitivity to gastric acid solved?
Addition of protective coatings to the drug that shields it from stomach acid and will dissolve in the intestinal tract where the drug can become active
Modification of penicillin e.g Penicillin G modified to penicillin V making it more stable in acidic conditions – made if less active against infections.
How is the issue of rapid penicillin removal from mammalian systems solved?
Larger doses are given to patients to raise penicillin levels within the body due to its low toxicity
Co-administer a second drug (e.g probenecid) - found to increase serum level of antibiotics by reducing excretion due to competition for active sites of excretion.
these methods can increase the time that antibiotics are maintained in the blood stream for 1-24 hours
What is Ampicilliln?
Whar are ampicillin derivaties?
Peniilin G with an amino acid added to its side chain.
Ampicillin derivatives: amino group replaced with other side chains to alter properties and create new antibiotics
How do ampicillin and ampilicin derivaties extend the spectrum of penicillins?
Modification allows ampicillin to effect gram negative bacteria because it can pass through porins found in the outer membrane of Gram negative bacteria and access the cell wall which is located inside the outer membrane and exert its action.
How does antibiotic resistance to natural penicillins appear?
Resistance to natural penicillin appears via beta-lactamases which can break down the antibiotic.
What are Ureidopencillins?
new penicillin’s designed to further broaden the spectrum of activity of this drug class
How do Ureidopenicillins broaden spectrum activity?
Active against P.aeruginosa - resistant and clinically important bacterium
Show activity against enterobacteria and some gram positives
Sensitive to B-lactamase activity
Can be co-administered with tazobactam (B-lactamase inhibitor) to increase their spectrum by allowing them to be effective in bacteria expressing B-lactamases, making them even more effective against P.aeruginosa, particularly those carrying a B-lactamase
How do B-lactamases bacteria resist natural penicillin?
Resistance to natural penicillin appears via beta lactamases which can break down the antibiotic.
How is B-lactamase antibiotic resistance resolved?
by co-administering B-lactamase inhibitors at the same time as beta Latam antibiotics (e.g penicillin) - resistance is inhibited by stopping the beta lactamase from breaking down the antibiotic
How are staphylococci bacteria resistant to penicillin?
due to their expression of penicillinase (specific B-lactamase)
What are Isoxazlylpenicillins? What is the most commonly used one?
Isoxazolylpenicilins (ozacillin, cloxacillin, flucloxacillin): group of semisynthetic B-lactamase resistant penicillin derivatives that are acid stable and active against primarily gram-positive bacteria - penicillinase resistant, insusceptible to B-lactamase activity.
Flucloaxcillin: commonly used and well absorbed when taken orally.
Describe the B-lactamse mechanisms of resistance to penicillin.
B-lactamases break down antibiotics by hydrolyzing the B-lactam ring rendering the antibiotics inert
How has MRSA staphylococcus aureus become resistant to penicillin?
acquired a gene encoding a penicillin binding protein that penicillin antibiotics cant bind to (mecA gene0 which codes for the PBP2a protein.
Bacterial growth continues - Penicillin binding protein can continue to catalyze crosslinking of peptidoglycan in the cell wall in the presence/absence of the antibiotic.
What are Cephalosporins?
Cell wall synthesis inhibitors
B-lactam antibiotics with a B-lactam ring
Similar structure to penicillin
How are Cephalosporins modifiable?
two modifiable side chains giving more versatility to scientists when creating modified cephalosporins.
Describe the benefits of Cephalosporins
Mostly stable to B-lactamases derived from staphylococci
Dont cause allergy in people who are allergic to penicillins via the same mechanisms
More cephalosporins than penicillin’s
Much versatility due to the ability to modify at two different sites.
Modifications at C-3 position have a greater influence on pharmacokinetic properties.
Alterations at either position can affect antibacterial properties
How are cephalosporins modifiable? Which modifications are favourable and why?
ability to modify at two different sites.
Modifications at C-3 position have a greater influence on pharmacokinetic properties.
Alterations at either position can affect antibacterial properties
Name the original Cephalopsorin.
Cephalosporin C: original cephalosporin - Was the starting point for a massive range of compounds within this family which is still expanding - 5 generations so far.
What are Carbapenems?
Major group of B-lactam antibiotics.
Carabpenem examples: Imipenem, Meropenem, Idoripenem, Ertapenem
What are the benefits of Carbapenems compared to other B-lactam antibiotics?
Structurally like penicillins/cephalosporins with three variable regions.
Broadest spectrum of activity of all the B-lactam antibiotics
Most stable against most B-lactamases
Broad spectrum - stable against beta- lactamases including the extended spectrum.
How are carbapenems administered?
administered parenterally by intravenous infusion.
Impipenem hydtolysed by the kidneys by via a dehydropeptidase into a nephrotoxic intermediate .
In mammals it must be co-administered with a dehydropeptidase e.g Cilastatin: inhibitor of impipenem metabolism.
Meropenem: stable to mammalian dehydropeptidase - doesn’t require co-asministration of an inhibitor. Both drugs administered by intraveneous/ intramuscular injection
How are Carbapenems used in hospitals?
reserved for life-threatening infections (in hopsitals where the caussative agent is unkown)
What are carbapenemases?
Carbapenem inactivating enzymes.
Most versatile family of B-lactamases.
Active against all hydrolyzable B-lactam antibiotics including penicillins and cephalosporins.
Most are resilient to inhibition by commercially viable B-lactamase inhibitors.
Describe resistance to carbapenems.
Bacteria (predmoninantly gram neg) emerged with carbapenemases.
Carbapenemases were initially idenitifed as species-specific – located on the chromosome and of lower concern clinically
More recent discoveries of plasmid-encoded carbapenemases including P. aeruginosa, A. baumannii and Klebsiella pneumoniae – makes resistance to these antibiotics a global problem with potential for rapid interspecies dispersion.
What are Glycopeptides?
Major family of antibiotics that inhibit cell wall synthesis
Complex heterocyclic molecules made of multi-peptide backbones that attach to different substituted sugars
Describe the mechanism of action of Glycopeptides.
bind to acyl-D-alanyl-Dalanine in peptidoglycan, preventing the addition of new material to the cell wall
Too bulky to navigate gram-negative outer membrane – cannot diffuse through the membrane, too large to travel through porins – cannot access their target of cell walls in these bacteria.
Generally, only active against gram-positive bacteria where the cell wall is outermost
Describe the structure of Vancomycin.
peptide backbone of glycopeptide with seven different modified amno acids bound together.
Disaccharide is composed of glucose and vancosamine bound to this backbone via glycosylation.
How is vancomycin administered?
Generally via injection into a vein - ensures systemic delivery as the drug is poorly absorbed when administered orally.
Must be delivered slowly over 1/2 to avoid complications.
What are the side effects of vancomycin?
Purified formations of vancomycin can cause renal and ototoxicity.
What is red man syndrome? How is it caused? How is it treated?
Erythematous rash of the upper body, head, and neck caused by rapid delivery of vancomycin (doses delivered in less than 30 minutes)
Can cause angioedema and cardiovascular collapse in severe cases
Caused by histamine release
Patients may be given antihistamines as part of the therapy before of after symptom onset to minimize/prevent effects
How is a patient receiving vancomycin monitored to monitor the chances of potential side effects?
Levels of Vancomycin in the blood may require monitoring under certain circumstances e.g patients on long-term or high-dose therapy or with potentially altered pharmacokinetic parameters- drug may be removed more slowly/quickly from the body
Minimum serum levels are monitored in pateints to ensure that vacomycin does not spend too much time in the bloodstream at levels higher than the minimum inhibitory concentration.
What is Teicoplanin?
Glycopeptide
Mixture of several closely related compounds with slight variations in the R group
What is the structure of Tecioplanin?
All contain the same glycopeptide core- two carbohydrates (mannose and N-aceytlglucosamine) are attached
Third carbohydrate (B-D-glucosamine) attached where the side chain varies to create slightly altered compounds
How is Teicoplanin administered?
Administered by injection into the muscle
What are the benefits of Teicoplanin?
Longer half-life in the body/fewer adverse reactions than vancomycin
Teicoplanin has similar activity to vancomycin
How are Glycopeptides used in hospitals?
As last resort
How does glycopeptide resistance occur?
Vancomycin-resistant enterococci (VRE)
Resistance most likely occurred in non-human pathogens and was transferred to enterococci on mobile genetic elements
The major mechanism of high-level resistance is altering the peptidoglycan structure so that antibiotics can no longer bind – cannot inhibit peptidoglycan synthesis
How do Glycopeptides treat resistant staphylococcus infections? What does this show about Glycopeptides?
The major mechanism of high-level resistance is altering the peptidoglycan structure so that antibiotics can no longer bind – cannot inhibit peptidoglycan synthesis
Glycopeptides recommended for treatment due to the emergence of methicillin resistant coagulase-negative Staphylococcus infections
Resistant Staphylococcus isolate screens show a large proportion are also resistant to teicoplanin but remain susceptible to vancomycin and vice versa with some VRE resistance mechanisms
Highlights that these glycopeptides have the same mechanims of action but are significatly structurally different and that not all mechanisms of resistance cause resistance to different kinds of glycopeptides
