lecture 1 Flashcards
antimicrobial
Any chemicals which kill or inhibit microbial growth in or on a body surface (Fungal, viral, bacteria…)
antibacterial
chemical that specifically target bacteria, killing or inhibiting its growth
state the sources of antibiotics
microorganisms like penicillin, synthesis like chloramphenicol, and semi-synthesis which is the most common, like amoxicillin.
most antibiotics work only on actively growing bacteria
what are latent infections
where the bacteria are present but not actively growing – so are in a dormant / persister state are hard to treat-
explain bactericidal, bacteriostatic, and selective toxicity
1-kill bacteria
2-slow down or stall bacterial growth
3-selectively kills or inhibits the target organism, whilst causing no or minimal harm to the host
explain the ideal properties and activities of antibacterials.
specific, selective, bactericidal, minimal emergence of resistance to the drug, along with pharmacological activities
Specific: the ability of a drug/chemical agent to interact with a defined target
Selective: selectively kills or inhibits the target organism, whilst causing no or minimal harm to the host as less selectivity means more adverse effects.
Pharmacological activities
- Non toxic to host
- Long plasma half life
- Good tissue distribution
- Low plasma protein binding
- Oral & parenteral
- No interference with other drugs
name antibacterial classification based on cellular targets
cell wall- major target and selective, bactericidal
protein synthesis- many drugs, exploit the differences between prokaryotic and eukaryotic ribosomes, selective, mainly bacteriostatic
nucleic acid- may drugs, different cellular machinery, selective, mainly bactericidal
cell membrane- few drugs as cell membranes are highly similar. few targets selective for bateria
name the classes of inhibitors of cell wall synthesis
Beta lactams-Penicillins, cephalosporins, carbapenems, monobactams
glycopeptides-Vancomycin, teicoplanin
Fosfomycin
cycloserine
bacitracin
explain peptidoglycan and where it gets its strentgh and rigidity
the peptidoglycan layer it is broadly similar in Gram positive and Gram negative bacteria
It’s made up of a glycan (or polysaccharide) backbone, which has short peptide side chains.
The polyscaccharide part is made up of two different glycans-
N-acetyl-glucosamine or NAG and
N-acetyl-muramic acid or NAM –
And these NAG, and NAM residues alternate along the chain and are linked together by strong glycosidic bonds.
This give the structure strength in the Horizontol direction
(These N.A.G. and N.A.M are also known as amino sugars )
Attached to each molecule of N-acetyl muramic acid is a short peptide side chain (a chain of amino acids) –
The peptide side chains then cross link to a neighbouring peptide on an adjacent peptidoglycan. This gives a strong bond in the vertical direction
The peptide side chain is shown here in the final structure as 4 amino acids, but actually it starts off as 5 amino acids, and the terminal amino acid is removed during the crosslinking step,
The two types of bond: the glycosidic bonds and the crosslinking between peptides are what gives the cell wall its rigidity in the horizontal and vertical directions, and help create the strong mesh like structure.
If you break down either the vertical rigidity or horizontal rigidity then you destroy the cell.
peptidoglycan biosynthesis
dont need to learn but learn if you have time
Beta lactams
all have beta lactam ring. the differneces are in the r groups( the ring attached to beta lactam and the side chains)
explain beta lactams 3 modes of action.
direct: inhibit the crosslinking of the peptide side chains
1-Bind to and inhibit action of transpeptidases usually known as Penicillin Binding Proteins (PBPs) -The drugs directly bind to the Transpeptidases – also known as the Penicillin binding proteins or PBPs which catalyse the crosslinking of the peptide side chains.
This inhibits the enzyme from catalysing the reaction, there is no crosslinking and you lose the rigidity of the cell wall in the vertical direction
Prevents X-linking prevents stable formation of peptidoglycan cell lysis
or
2-Get incorporated into peptide side chain
Prevents X-linking prevents stable formation of peptidoglycan cell lysis
If you look at their structure it is similar to the last 2 amino acids of the peptide side chain on the peptidoglycan and the drug can be incorporated into that peptide sidechain
this has the same effect –in that if the drug is in this position and not the amino acids
It again inhibits cross linking by the Penicillin binding proteins and effects the rigidity of the cell wall.
incorporation into the peptide side chain is the second direct mode of action.
indirect mode of action: they stimulate enzymes called autolysins inside the bacterial cell, which causes the bacteria to break down their own cell well, which again causes the cells to lyse.
why do beta lactams work better on gram positive bacteria
beta lactams need to interact with PBP, which is an enzyme on the outer membrane, to work. in gram positive bacteria, it is easier as the only obstacle between the PBP and the drug is a meshwork of peptidoglycans which is not a solid barrier. But in gram negative bacteria, it is no as easy, since the drug has to pass through a cell membrane before interacting with the PBPs, which they can only do via porin channels, which only small or hydrophilic structures can pass through( my answer)
Beta Lactams can work in both Gram positive and Gram Negative bacteria- but we have more which can work on the Gram Positive bacteria
Beta Lactams are targeting an enzyme on the outer surface of the bacteria’s cytoplasmic membrane.- they don’t need to enter the cell
In Gram +ve bacteria they just have to penetrate the cell wall – which is a mesh like structure, its’ not a solid barrier – they can easily reach the outer surface of the cytoplasmic membrane and bind to the Penicillin Binding Protein.
For Gram -ve bacteria -to reach their target they first have to pass through the outer membrane – which they can only do by entering through the pores in the membrane- porin channels .
Only smaller hydrophilic antibacterial agents are able to pass through these channels- it is harder for larger molecules/ or hydrophobic to reach their target.
Depending on their precise structure some Beta lactams can pass through these channels and others can’t, and so only some types of beta lactam antibiotic can treat some Gram negative bacteria.
Eg pseudomonas has small porin channels (answer in the slides)
Beta-lactams need to interact with penicillin-binding proteins (PBPs), enzymes located on the outer surface of the cytoplasmic membrane, to exert their effect. In Gram-positive bacteria, the only barrier is the peptidoglycan layer, which is a porous, mesh-like structure. This allows beta-lactams to easily reach PBPs.
In contrast, Gram-negative bacteria have an additional outer membrane. Beta-lactams must pass through porin channels in this membrane to reach PBPs. These channels restrict access based on size and hydrophilicity, making it harder for larger or hydrophobic beta-lactams to penetrate. As a result, only certain beta-lactams, like carbapenems, are effective against some Gram-negative bacteria. For example, Pseudomonas aeruginosa has small porin channels, further limiting drug entry. ( chat gpt answer)
glycopeptide antibiotics, how do they work?
large gram positive specific antibiotic ( because they are very large)
Glycopeptides target cell wall synthesis and again target the peptidoglycans
Vancomycin iworks in 2 ways:
1 Vancomycin binds very tightly to the last 2 amino acids on the peptide sidechain of the peptidoglycan monomer. They are normally 2 alanine residues. (Ala-d- Ala)
This means that again it prevents crosslinking of the peptide sidechains- the pbp enzyme cant bind and can’t cleave the terminal amino acid, so cross linking can’t occur
2 Vancomycin also prevents the peptidoglycan monomer being attached on to the peptidoglycan chain- it inhibits the glycosylase enzyme from working.
And prevents the glycan chain forming. If you remember glycosolases catalyse its addition onto the peptidoglycan structure by the the formation of glycosidic bonds between the sugar residues.
If the Vancomycin, which is a large molecule is attached it is very big and so prevents the glycosylases working
inhibitors acting on cell membrane and their example
polymyxins-
polymyxin E (Colistin)- fell out of use due to severe nephrotoxicity
Lipopeptides-
daptomycin (Cubicin)
