In this video we discuss the mechanism by which the Folate antagonist antibiotics, which include the sulphonamides and trimethoprim, achieve their bacteriostatic effect.
Welcome back to the next video in which we are discussing folate antagonist antibiotics okay so in the previous video what we discussed is the sulfonamide antibiotics and how they work and we saw that the way that the sulfonamide work is that they inhibit this enzyme dihydrate or it’s synthetase inside bacterial cells and this enzyme is important in the biosynthetic
Pathways for folic acid okay so by walking this enzyme you block the synthesis of photographs of hence why sulfonamides are considered folate antagonists antibiotics because they antagonize the folate pathway now remember folic acid is so important because it’s essential for the function of the enzymes which make rna and dna nucleotides and without the function of
Those enzymes you’re not going to make dna and rna nucleotides without dna and rna nucleotides you can’t synthesize dna and rna hence you can’t make proteins and you can’t replicate your genome hence you can’t define so that’s why this or fun amides have a bacteriostatic effect in this video what i want to start off with is a discussion of sulfonamide resistance in
Bacteria which is a big problem which now a huge limb limits the use of the soft onam identify optics then what i want to do is discuss the other example of third item tagging is antibiotic which is trimethoprim okay so let’s discuss resistance then – so follow mine so resistance how does it actually occur well in the bacterial cells that are resistant to sulfonamide
So if i have let’s say a bacterial cell here okay and i chuck sulfonamide antibiotics that’s it and they have absolutely no effect then of course i would call it a salami resistant bacterial cell it still divides away quite happily okay it’s though that synthesis pathways aren’t blocked it’s therefore is a source on a virus resistant bacterial cell water actually
Is allowing it to resist the effects of myself on the mite why i am i so follow minds in not having the effect they should on the dihydrate right synthetase enzymes in this resistant bacterial cell well resistant bacterial cells we thought have found that they have a new form of the enzyme okay so i’ll draw this here they have a modified form of the dihydrogen
Synthetase enzyme so i’ll draw it now in red here and i have a new red pen okay so here is this new form of the dihydrate alright synthetase enzyme so again this is d h ps but this is a slightly modified form and now this might be modified form this slightly modified form of the die hydra to write synthetase enzyme it’s no longer sensitive to the so far the mice
They cannot bind to it anymore and competitively inhibit the access of para i mean they’re benzoic acid anymore okay so the sulfonamide has become totally useless now how did bacterial cell acquire the ability to make this new form of dying hydrogen synthetase that is resistant to soar follow mais well it’s encoded in plasmid dna so around the bacterial cells
They generally have a huge great genome which is circular so they have a massive great chromosome which is a circular chromosome so it’s very different 12 chromosomes in our chromosomes human chromosomes we of course have 46 of them again the dna is a massive great linear piece of dna a huge great piece of linear dna but the linear it doesn’t fold back on itself
In the case of bacterial chromosomes the thing folds around into a great big of loop okay so this in red here this is supposed to represent my major portion of this bacterial cell genome which is the chromosomal dna so usually back to ourselves have one or two chromosomes okay so i’ll just show this one with a single chromosome so this is the chromosomal dna but
Remember bacterial cells can also have tiny little loops of dna as well and that are in addition to the chromosomal dna and these neural loops of dna that are much smaller than a great big loop of chromosomal dna here these are known as plasmids now bacterial cells can have a huge number of different plasmids and they can acquire them from other bacterial cells
So there’s this phenomena of bacterial conjugation where bacterial cells give plasmids to neighboring bacterial cells so they can interchange their plasmid genomes okay so the new form of the die hydra trait synthetase enzyme which is no longer affected by the so follow my antibiotics the gene encodes it is in a plasmid ok so originally in the bacterial population
So if we look at all the bacteria on the planet long before the use of sulfonamide antibiotics so let’s go back into the nineteenth century before we used sulfonamide antibiotics if we looked at the entire bacterial population on the planet there again gone to all the different forms of bacterial species that infect humans the presence of this plasmid containing
This new form of dihydrate synthetase which was not going to be affected by sulfonamide antibiotics would have been very rare so they few bacterial cells would have actually had this plasmid with this new form of dihydrogen synthetizer however what happens of course when you apply a selection pressure which we did when you start using a huge number of sulfonamide
Antibiotics against bacterial populations you apply a huge great selection pressure and then it’s just darwinian evolution you kill off all the bacterial cells that do not have this new form of dihydrate right synthetase because they are going to no longer well you don’t kill them of course you it’s bacteriostatic you damage their reproductive potential you stopped
Them from being able to divide which obviously damages their reproduction the ones which do have the new form of dihydrate rights and pertains they will now divide more than the ones that have not got it and therefore they will their frequency in the population there but proportion of the population with dihydrogen details of this new decline with increase over
Time okay so it’s classical darwinian evolution of the population so the population overall then evolved since this trait of having this dihydrate rate synthetase which isn’t affected by the sulfonamide antibiotics becomes more prevalent okay because it enables the bacterial cell to better survive and reproduce in the environment in this environment where humans
Are checking these horrible droves of them okay right so that’s what has happened darwinian evolution has occurred the proportion of bacterial cells in the population with this modified form of dihydrate synthetase which is resistant to sulfonamide antibiotics is hugely increased and now often when you chuck so fond of my dad’s plastics of a certain population
Of bacteria that are maybe causing some disease they might not kill or what i might not have an effect on a huge number of them which do indeed have this dihydrogen synthetase which isn’t effective base for follow minds so there is some fun amide resistance in bacterial cells let’s now move on to the mechanism by which trimethoprim this other third agent agonist
Antibiotic actually works okay so tri methyl prim now trimethoprim is often abbreviated down to tmp okay and it’s also going to work by affecting the phone a pathway however it’s going to work at a later stage than the sulfonamide so the sulfonamides worked by stopping the synthesis of folic acid by pivoting by hydrogen through the tails in the bacterial cells
Trimethoprim is going to work to stop folic acid actually having the effect that we want it to have to remember though the cancer is important in the bacterial cells because we need it for the enzymes that make the nucleotides of dna and rna to actually work but in fact that’s an oversimplification i’m going to now make the story slightly more complicated in
A slightly closer to the truth it is not phonak acid quite that those enzymes leave instead it is a form of folic acid known as tetrahydrofolate okay i’ll tell hydrofluoric acid so in fact what needs to happen is folic acid needs to be converted firstly into dihydrofolate or die hydrophobic acid now let me just establish what the difference between folate and
Folic acid is and nicely we have the picture of folic acid here okay so folate and folic acid what is the difference between these two folate is the conjugate base of folic acid so it’s just acids and alkalis and bases and all of that and so here we have seen the reason that folic acid is indeed an acid it has these two carboxylic acid groups one here and another
One here okay and these are capable of donating protons away into solution now the molecule when it has the protons attached to it that is known as folic acid okay that is actually capable of donating protons away into solution however once it’s actually donated the protons away into solution then you now have the negative charges on these oxygen atoms here that
Is no longer called folic acid the reason is it’s no longer an ax there that it can’t actually donate any protons away into solution anymore because it already has donated its protons away into solution it doesn’t have any more protons to give there is now called a foal ain’t so phone eight is what’s known as the conjugate base of folic acid it’s the folic acid
Once it’s actually done each of its protons away into solution once it’s actually done what assets do the thing that’s left over is called the conjugate base because actually it’s no longer that’s an it’s a base because onto these oxygens with the negative charges you can actually put protons from solution and such molecules which can accept protons from solution
Than those in the spaces so in fact all assets once they’ve donated that frozen away become a base and that’s known as the conjugate base and that says okay so folate is just the name for the photic acid molecule wants its donated its protons away into solution now under physiological ph a lot of the folic acid molecules will donate their protons away into solution
And therefore will exist as folate molecules rather than throwing acid molecules which is why people often talk about the late rather than photic acid however – all extensive purposes folic acid and folate of the same molecule that the two sides of the same coin if you like okay so that’s why people have to refer to phone eight over the folic acid so i’ll put this
Here folic acid or phone eight is going to be converted into dye hydrophobic with folate which you could call dye hydrophobic as that if you wish okay which will then be converted into tetrahydrofolate people usually just use folate rather than folic acid but you’ll crude again in tetrahydrofolate replace the phone with folic acid it would not be wrong to do that
Okay and the short d h f stands for dihydrofolate and tetrahydrofolate is shortened down to t hf like so okay and this is t h f that is really important for the function of those enzymes which are going to synthesize the nucleotides so in order to actually use folate to actually help these enzymes which to produce the nucleotides of dna and rna you have to first
Be converted into dihydrofolate and then into tetrahydrofolate and trimethoprim is going to inhibit the enzyme which carries out these conversions here and the enzyme which carries out these conversions is known as dihydrofolate reductase or dhfr so this enzyme is known as the dye hydro folate reductase so inside the bacterial cells they have this enzyme called
Dihydrofolate reductase which converts the boland folic acid i’m trying to now combine folic acid and folate in together in my head so excuse me if i make that mistake again so it’s going to convert though the capsid molecules into dali hydrofluoric acid molecules which are then going to be converted into tetra hydro fluoric acid molecules and the tetra hydrophobic
Acid molecules are now the molecules that are actually essential for the function of those enzymes which create the nucleotides with dna and rna ok trimethoprim this antibiotic is going to go in this the bacterial cells and it’s going to inhibit the dihydrofolate reductase enzyme and therefore stop the conversion of folic acid molecules into tetra hydrophobic
Molecules you’re never going to run out of tetra hydrophobic molecules and the enzymes which create the nucleotides of dna nr and they are therefore going to stop working and you’re therefore have the exact same effect as these sort for minds have you will have a bacteriostatic effect okay so trimethoprim is also therefore referred to as a folate antagonist the
Reason being that it antagonizes the folic acid pathway it attacked the bacterial cells it stops them being able to divide by damaging their handling of bollock acid okay right what i want to end this video on them is just mentioning a really important combination which is the drug code trim oxes all again you’ll often hear about this drug is often prescribed
Cotrim oxes all is the combination for sulfamethoxazole and trimethoprim and often some people also write code from oxes all as smx /tmp because it’s offer me foxes or witches as i told you earlier abbreviated down just sm acts with trimethoprim which is abbreviated down to tmp so cotrim oxes all it’s the combination of sulfamethoxazole a powerful so follow my
With trimethoprim is to folate antagonist antibiotics and so for me foxes all will inhibit dihydrate to rate synthetase trimethoprim will inhibit dihydrofolate reductase they’ll inhibit both parts of the folate pathway here therefore you’ll have a double effect and you really will stop the production of tetrahydrofolate and therefore you really will damage the
Performance of these enzymes which are involved in synthesizing nucleotides and together they will have a stronger bacteriostatic effect than the individually oh it’s a code from oxes oh that’s the combination of trimethoprim so the trim is for trimethoprim and the oxes or is then the ending of sulfamethoxazole okay and with that i will finish this video on throat
Antagonist antibiotics i hope that you have learned how the folies antagonist antibiotics actually achieve a bacteriostatic effect and you understand that these antibiotics will be useful in people whose immune system is up to the job of getting rid of the bacterial infection once you’ve stopped it getting any worse okay but if you are dealing with someone who is
Immunosuppressed and whose immune system is not up to the job of clearing the bacterial infection once you’ve stopped it getting any worse then you bactericide rounds button which these two classes are not ok so we’ll end the video there
Transcribed from video
Folate Antagonist Antibiotics Part 2 By Elliot Nicholson
