Antibiotic Classes & Modes of action Flashcards
Macrolides and examples. State Mechanism, What it’s active against. Bacteriostatic or sidal?
Bind to 50s subunit of ribosomes; inhibiting peptidyl transferase and so blocking peptide elongation.
Macrolides are generally good for respiratory infections and soft tissues as it can penetrate human tissues well. It’s an alternative to penicillin allergic patients.
e.g Erythromycin and Clarithromycin
Erythromycin: in particular and is also used for staphylococcal infections
Clarithromycin, a derivative of erythromycin, is used along the same lines but has additional activity e.g. against Legionellaspecies and chlamydiae.
Bacteriostatic. Can be Bactericidal at high concentrations.
Chloramphenicol - Activity - Side effects - susceptible microorganisms. Static or Sidal?
Diffuses across cell membrane and Binds to 50s subunit of ribosomes inhibits protein synthesis inhibits peptidyl transferase, so no peptide elongation. In terms of activity - it has broad-spectrum range activity.
Penetrates the cerebrospinal fluid well, Therefore it’s used to treat meningitis.
It is Bacteriostatic, but when treating gram +ve cocci, it is bactericidal
Side effect: a bone marrow does not produce cells
Tetracyclines. action - indication - examples and side effects. Static or Sidal?
Bind to 16s subunit of ribosomes but interefers with 30s ribosome subunit, inhibiting tRNA.
e.g doxycycline
Indicated for Acne Vulgaris,
Side Effects: Nausea, Diarrhoea and Renal Concern. It can accumulate in bones and teeth. Teratogenic.
Bacteriostatic
Oxazolidinones
Bind to 50s subunit of ribosomes; inhibit tRNA binding
Rifamycins MOA/Activity/Side effects
inhibit bacterial DNA-dependent RNA polymerase, preventing transcription of mRNA
Activity: Rifampicin crosses the BBB and is used to treat meningitis
It’s Broad Spectrum and can be used on both G+ve and G-ve Can also be used in combo with isoniazid for Mycobacterium Tuberculosos
Side Effects: Fever, Loss of Appetite, Malaise
Quinolones
Inhibit topoisomerases
Nitroimidazoles
Reduction in anaerobes produces radicals which cause oxidative damage to macromolecules e.g Metronidazole
isoniazid
inhibits mycolic acid synthesis in Mycobacteria
Bacitracin
inhibits regeneration of lipid barrier
cycloserine
inhibits D-Ala-D-Ala formation
Glycopeptides and an example. What are they only effective against? Indications?
prevention of incorporating subunits into growing peptidoglycan wall by binding to the D-ala D-ala of the short peptide chain on N-acetylmuramic acid
E.g Vancomycin
ONLY effective against Gram-positive (both anaerobes and aerobes) because they’re too bulky to penetrate outer membrane of the G-ve species
They’re reserved for seriously ill patients with G+ve species. e.g MRSA and C.difficule
name 3 B-Lactams
Penicillin, Cephalosporin, Carbapenems
Role of B-Lactams with an example
inhibit transpeptidase crosslinking of Peptidoglycan strands. Beta Lactam binds to penicillin-binding proteins.
This increases osmotic pressure, activating autolysins that degrade the cell wall.
There is a change in cell shape and size
Leads to the death of the bacterial cell
e.g Benzylpenicillin
Polymixims
disrupt bacterial membranes
Sulfonamides
DHTS (dihydropteroate synthetase) inhibitors
Trimethoprim
DHFR (Dihydrofolate reductase) inhibitor
Daptomycin
Disrupts Gram +ve plasma membrane
Bind to 50s subunit of ribosomes; blocking peptide elongation
Macrolides
Binds to 50s subunit of ribosomes; inhibits peptidyl transferase
Chloramphenicol
Bind to 30s subunit of ribosomes, inhibiting tRNA binding
Tetracyclines
Bind to 50s subunit of ribosomes; inhibit tRNA binding
Oxazolidinones
inhibit bacterial RNA polymerase
Rifamycins
inhibit topo-isomerases
Quinolones
Reduction in anaerobes produces radicals which cause oxidative damage to macromolecules
Nitroimidazoles
inhibits mycolic acid and synthesis in Mycobacteria
isoniazid
inhibits regeneration of lipid barrier
Bacitracin
inhibits D-Ala-D-Ala formation
cycloserine
prevention of incorporating subunits into peptidoglycan wall
Glycopeptides
Penicillin, Cephalosporin, Carbapenems
name 3 B-Lactams
inhibit transpeptidase crosslinking of Peptidoglycan strands
Role of B-Lactams
disrupt bacterial membranes
Polymixims
DHTS (dihydropteroate synthetase) inhibitors
Sulfonamides
DHFR (Dihydrofolate reductase) inhibitor
Trimethoprim
Disrupts Gram +ve plasma membrane
Daptomycin
state all the classes of antimicrobial agents
Aldehydes
Oxygen species
Halogens
Phenoliccompounds
Alcohols
Biguanide-based compounds
Quaternary ammonium-based compounds
Organic acids
what class is the most aggressive out of the Antimicrobial agents? give an example and how it works
Aldehydes, e.g Glutaraldehyde: It treats surfaces and temperature sensitive medical and dental equipment.
Works by cross linking proteins, This therefore prevents protein synthesis of microbial macromolecules. It shows broad efficacy of action, and is rapidly antibacterial, fungicidal, virucidal.
It is so active that it can be used as a chemosterilant.
Pros: Effective at low temperature, highly active and low surface corrosiveness
Cons: Can cause skin irritation
name some broad spectrum antibiotics
(the three) B-Lactams, Tetracycline, Chloramphenicol, Quinolones, Macrolides
name some narrow spectrum antibiotics
Glycopeptides, Aminoglycosides
discuss an example of a biguanide based compound. comment on acivity, strengths and weaknesses
chlorhexidine. Antiseptic mouthwash used to treat a wound. It is rapidly absorbed through bacterial/yeast cells
- acts primarily on cell membranes = leads to cytoplasm content leakage
Thus - there is a loss of function and cell structure.
Chlorhexidine directly inserts into cell membrane bilayers
Activity: Broad spectrum antibacterial activity. Less effective against fungi.
Strengths: relatively little irritation of skin or mucous membranes. Effective in preventing spread of pathogens in hospitals.
Weaknesses: can cause eye problems and can damage the inner ear. It can also cause anaphylactic shock in extreme cases.
what strategies emerged to deal with penicillinase producing strands? add examples
- design of penicillinase-tolerant penicillins e.g flucloxacillin
- development of penicillinase inhibitors e.g clavulanic acid, sulbactam and tazobactam
the penicillinase inhibitors have little antibacterial activity alone, but bind and inactivate beta-lactamases/penicillinases. Allows a combined approach of penicillin (antibiotic) + tazobactam (inhibitor)
can penicillins target only G-ve/G+ve or Both?
both
give the structure for clavulanic acid
what is co-amoxiclav?
Amoxicillin - similar and often combined with clavulanic acid. It is active against certain gram negatives e.g H.influenzae. The addition of the B-lactamase inhibitor clauvulanic acid increases the spectrum of antimicrobial activity
state the three locations on a bacterial ribosome for attack
APE:
A (aminoacyl) site - where after initiation each ‘new’ aminoacyl- tRNA attaches
P (Peptidyl) site - where the the peptide bonds are formed
E (Exit) site - where tRNA leaves the ribosome
Aminoglycosides - Mode of action - Suseptible organisms - Side effects - drug examples
Aminoglycosides are actively transported into bacterial cells growing aerobically. They bind irreversibly to 30S subunit, Inhibiting protein synthesis. Interruption of translation results in misreading of mRNA. This leads to NO proteins or DEFECTIVE proteins.
They are active against staphylococci and mycobacteria. However they’re innefective against anaerobically respiring bacteria which have innate resistance.
indicated for Pseudomonas Aeruginosa
Examples are gentamicin, and streptomycin. Side effects: Renal Toxicity, Dizziness, Hearing loss, Nausea and Vomiting.
What is a side effect of penicillins?
suggest a drug class (and examples in that) to give to a patient with a penicillin allergy.
S/E
rash, diarrhoea, abdominal pain, nausea, vomiting, hypersensitivity.
Alternatives
Macrolides - erythromycin and clarithromycin
Antibiotics inhibiting nucleic acid synthesis have three main interrupting strategies. What are they?
- Binding to DNA Topoisomerases
- Preventing transcription by binding DNA-dependent RNA polymerase
- Distupting bacterial DNA through cytotoxicity
what are the four overall strategies of bacteria activity. Give examples
- Disrupt bacterial cell walls - e.g Beta Lactams, Glycopeptides
- Inhibit protein synthesis e.g Aminoglycosides, Tetracyclines, Chloramphenicol, Macrolides, Clindamycin
- Inhibit nucleic acid synthesis e.g Quinolones, Rifampicin, Methonidazole
- antimetabolite activity e.g Trimethoprim, Sulfenamide
Metronidazole indication - mode of action. Static or Sidal?
Indicated for C.Difficile and B. Fragilis. It is only active in anaerobic bacteria and the drug is cytotoxic. It converts oxidoreductase into a mutagenic product which binds to DNA and destbilises the DNA Helix, causing it to break.
Bactericidal.
Give an overview of the mechanisms of antibiotic resistance
- Metabolic bypass-resistance (alters the enzyme in a metabolic pathway targeted by the abx)
- Over production ( the bacteria produces more of what is being targeted, so the abx is overwhelmed)
- Reduced uptake (e.g Beta-lactams reduced uptake)
- Efflux pumps (e.g S.Aureus has efflux pumps for fluoroquinolones)
- Alteration (e.g of the receptor or target site)
- Destroy the Abx (Beta-lactamases)
- Modify the Abx - e.g aminoglycosides made less able to produce oxidative radicals)
name two elements of a bacteria that can be transferred by horizontal gene transfer
Plasmid
Transposons
what are the pros and cons of multiple horizontal gene transfer?
There is an increased metabolic cost to the cell, this can affect cell fitness. However there is an increased ability for the cell to resist more than one of a particular number of antibiotic challenges
State 4 ways we can maintain the effectiveness of antibiotics
- Make them less generally available (e.g prevent agricultural use)
- Antibiotic rotation
- Resistance surveillance
- stop innapropriate use of antibiotics
name two Quinolones, Mode of action, activity, side effects
e.g Ciprofloxicin - Broad Spectrum
Fluoroquinolones - Narrow Spectrum (Gram Negative Enterobacteria, UTI)
In Gram -ve cells = DNA Gyrase is the target
In Gram +ve cells = Binds to DNA Toposiomerases to trap them. This affects supercoiling processes: Bacteriostatic.
if it breaks bacterial DNA this can result in cell death. Bactericidal
nausea, vomiting, diarrhoea, abdominal pain, headache, lethargy, insomnia
What is Amphtotericin B and what’s it indicated for. State MOA
Broad Spectrum Antifungal. It exhibits selective toxicity Binding to the ergosterol in fungal cell wall membranes, not cholesterol in human cell walls. It damages the fungal membrane, causing pores. This compromises the membrane integrity, leading to leakage of fungal metabolites
Indicated for Candida Albicans
Give an example of an azole drug, stating how they work
Terbinafine - Inhibits egosterol synthesis
how does the malaria parasite operate and how are qunine and chloroquine throught to work?
As part of their cell cycle, malaria infects blood cells. They’ll use haemoglobin as a source of amino acids. Haem remains intact. The haem is toxic and they’ll detoxify it.
Both quinine and chloroquine are thought to act to prevent detoxification of haeme in the parasite > this means the haeme remains and as such is toxic ultimately through cell lysis.
Clindamycin mode of action and what is it active against?
Binds to 50s subunit and inhibits protein elongation. Active against Staphylococcus (a G+ve) and Anaerobic G-ve
How does Metabolic bypass give bacteria resistance? - Give an example
How?
Bacteria alters enzyme in the metabolic pathway targeted by the abx
Example?
Mutagens give bacteria -> trimethoprim-resistant variants of dihydrofolate reductase genes
∴ bacteria bypasses the block trimethoprim causes on the non-mutated version
How does Overporduction give bacteria resistance? What example
How?
Bacterial cell makes more of what an abx is targeting:
Hence abx gets used up faster
Example?
Overproduction of a specific penicillin-binding protein (PBP-4)
e.g increases beta-lactam resistance in S. auereus by “mopping up’ the bacteria
How does reduced uptake give bacteria resistance?
Bacterial cell takes LESS Abx
- abx causes LESS damage to the bacteria
How des efflux pumps give bacteria resistance? E.g?
How?
Efflux pumps to get rid of as much drug entering the bacterial cytoplasm as possible
Example
P.aeruginosa has multi-drug efflux pumps to efflux out many different types of abx
(Pseudomodas infections are hard to treat!)
How does Alteration give bacteria resistance
How?
Bacteria alters the target site of abx
Example?
Mutations in chromosomal genes coding for ribosomal subunits can alter the abx target
Give an example of how modifying the antibiotic give bacteria resistance
Aminoglycoside abx resistance is due to modification of Abx structure as a result of 3 classes of enzymes
How do patients make antibiotic resistance worse?
- Patient non-compliance can lead to -> resistance
- By not completing their course -> suboptimal therapy, it makes bacteria sensitive to the Abx ∴ allows bacteria to emerge as resistant.
Where on the bacterial genome has resistance arisen? How does this fit in the bacterial survival.
Firstly, Antibiotics are needed to give selective pressure and favour resistant strains in survivng.
-
Chromosome -> contains all genes required for cellular maintenance + growth
- Only the specific bacteria will become resistant
-
Plasmid -> DNA molecule that replicates independently from the chromosome
- Can move between cells -> CONJUGATION
- of the same or DIFFERENT species!! > leads to acquired resistance
- can be multi-drug resistant = THREATHENING! Thrives in hospitals where lots of Abx is used
- Can move between cells -> CONJUGATION
How do I maintain the effectiveness of currently available agents? What factor do we consider when choosing an antibiotic to use?
Maintain effectiveness
- Make Abx generally less available
- Abx rotations
- Resistance surveillance
- Stop inappropriate use of Abx use
Choosing an Antibiotic is based on
- Pathogen susceptibility
- Cost
- Side effects
- Impact on host microbiota
Give a whistle stop tour on how to select an Antibiotic for an infection
Selecting an Abx to Treat an Infection
First = Identify the pathogen -> via undertaking tests in the Diagnostic Microbiology Lab
- Sample is received
- The specimen is look under the microscope to see what pathogens are likely in the sample
- This indicates what:
- Growth condition should be used
- Growth media should be used
- After incubation -> colonies of pathogen are recognised by their phenotype, identifying the pathogen
- Microscopy confirms OR denies this identify based on cell shapes + staining
- Staining -> Gram +ve OR Gram –ve
- Shapes -> Bacillus(rods) or Coccus (spherical)
- Often a mixed culture. Next step = derive a pure culture
