Okay. So today we'll start um talking about salva synthesis inhibitors. So as last time we spoke about the principles of antique therapy and towards the end of it we talked about classification and among that first few we said that there are cellos inhibitors there are protein sensors there are antabolides then there are drugs which affect the DNA synthesis so nucleic acids and inhibitors so in in that series the first one is on sale synthesis inhibitors. So by the end of session you should be able to classify the cells inhibitors uh discuss their structural activity relationship uh like especially with the better active antibiotics how the structure is related to their activities and uh if you don't remember then we can revisit the physiology of physiology of cable synthesis. Have you done it in microbiology? Yes. Yeah. So, so then you know it huh and and we will explain the mechanical action of petroleum antibiotics based on that and uh we'll talk about the mechanism of resistance in these antibiotics uh like against these antibiotics and we'll talk about the role of betalact inhibitors in combination with betalact antibiotics and we'll talk about some clinical uses and adverse effects of betalact antibiotics and macro So classification of antibiot we we last time spoke that there are cerosins inhibitors which include betalactum drugs and non betalum drugs. So, so there are four types of four classes of betalactum drugs which include panicellins, fellowspins, carbopen swams. I'm sorry for today it becomes very dry and so many new names and then there's like one drug in this class which inhibits the cell synthesis but is not a betalum drug. So you can call it non betalum drug. It's it's like it's one of them is vampy which we'll be talking about. And then you have protein inhibitors. So you'll have two lectures on protein inhibitors and we'll go into details at that time. And then you acid synthesis inhibitors like chloropols and you have anti metabolites try. So today we are going to talk about cell wall synthesis inhibitors. So how do you classify as I said so in in among cell wall sensors we have betalactum antibiotics. So, so their structure contains a ring which we call beta electron ring. So all the antibiotics which have that ring we call them better antibiotics and and they inhibit the cerosis at a particular step and then there's another drug which inhibits seros synthesis but at a different step because it's inhibiting seros so it comes under seros synthesis inhibitors but it's not a better electrom which is wencomptide so you can call non betalcto antivirus in that class so beta antibiotics again are further classified into four classes like penicellin, syphalosporins, carbopenants, monovacts. Again all of them have beta like temporary and then there are further types of penicellins. There are further classes of uh syphilosporins which are like five classes or five generations. We call them first generation, second generation, third, fourth and fifth generation. Today you'll have so many new names. I'm sorry. I'm the one who's starting this spell of contra. So, so this week you'll help me but like like in the coming weeks some of this hatred will be shifted to other people. Huh? But this we will be focused on. So in better antibodies we have panic, sephalosporins, carbopen and monopactums and it's being recorded. So I have started the recording. I had stopped in the beginning but then I started and so let's start with panic. So you know this guy And what did he do? Who said invented? Someone said invented. He discovered. What did he discover? So he was the one who discovered penis which changed again. Remember yesterday as well when the first antibbody was discovered by Paul. Yeah Paul alish but it was strictly speaking it was not antibiotic. It was antibacterial but it was not antibiotic. It was again organic compound sulas or something kind of sacin and because it was very toxic compound. It was arcenic containing compound but it was kind of the first of effective antibacterial therapy and it was I think came into use around 1910 1910 around that time. So it was the kind of first modern antibacterial drug and it was used to treat syphilis and some other infections but still speaking it was an antibiotic and it was very toxic as well. But once we had the discovery of peniselline and around World War II it came into common use especially for the soldiers and after so it was very effective and it was not toxic. So then like everybody started using paras. So this is sir Alexander Alexander Fleming and what was he doing? How did he discover paraser? not by accident. So he was culturing by accident. So he was culturing some bacteria probably for some of the bacteria he was culturing them. is growing there. And so on one of the following like one of the the culture dish he noticed that there was zone of inhibition like the bacteria were not growing and at that point like by accident some mold had grown or some mold drop on that area and because of that mold uh he noticed in that area the bacteria were not growing. So he named that uh mole as paracelium I think and and so and he thought of they need something inside this m this mold mic something which is inhibiting the growth of this bacteria that's how we discovered and obviously they must they must like more on it and they purified it so so he's he's known for that and it saved lots of lives like probably hundreds of thousands of lives. So it's important to know the historical perspective. So penistins were the first antibodies discovered as natural products and and remember see Nobel prize and he was giving his Nobel prize. So whenever these Nobel go get their Nobel Prize so they gave a speech and those speeches are available online. So in 1945 from that time in his speech he spoke about resistance at that time and those are the people who really think about the visionaries. So see he not we say by accident but like accidents happen everywhere but like only if you notice that someone else might have just thrown out that culture you know mean never thought about that. So he was in in that speech he was talking about resistance. So these were the first antibiotics discovered as natural products from the mold panicium and it was happened in 1928. Sir Alexander Fleming at St. Mary's Hospital in London when he was cursing stuff for years and he noticed don't have any. So again when you grow on something uncultured and then you put antibiotics and then you see if the bacteria are growing if they're growing then they are resistant to that antibiotic. If they're not going there and they sensitive to that antibiotic and you call that like as like the AO which is deficient of the growth you call zone of inhibition. So he noticed that zone of inhibition where mold spores were growing. So he named that mold as penicium glum and was determined and that the secretion of the mold was effective against gram positive bacteria. Superman structure consists of a thiozolidine ring fused with a betalactum ring and then it is attached to a side chain. Okay. Through the linkage and and these side chains determine many of the antibacterial and pharmacological characteristics of a particular type of penicellin. You see the penis and all other betum antibodies have a common thing which is betalactum ring which is very important for their antibacterial effect. Without betam ring if it's not intact the antibbody will not work and that's how the penises are betteres from the bacteria they inactivate these antib. So that's the that's what is needed. But then why these antibodies are different? Why their effects are different? If you need better which is same in all of them then what makes them different? Why like there are so many antibiotics in in this class better antibiotics and all of them have different properties and different spectrum. So, so there is something we'll talk about that and it's related to their structure. So, again you have this is the better ring and this is the theine ring and and this is the side chain. This is better ring the zolid ring and and that was the side chain and we'll talk about that. So you know the how the cell walls are synthesized. So cells are made up of which we don't have. We don't have cells and we don't have and this is different in positive and negative. Both of them have cells. They don't have both of them have cells. negative outer membrane. And what about silver itself? Is it different than positive? Which one is thicker? Thicker wall. Huh? Because you have thinner wall. But both of them have it. Okay. So that again changes the the like how different drugs would act on them. Uh Dr. Do we have to memorize like the structure of the drugs also? We will not talk about this. This is a one representative structure of all the penisins are like better. So this is what you need to know and and again I don't want you to draw this whole thing. It's like you need to know okay there's a better electronic there's a side chain and there's a thio so we need to be able to recognize yeah I won't ask you in an essay you okay make the structure with exact like representation of all those carbons and hydrogen's and nitrogen. No, but yes, you should know that okay, there's a beta ring and there's a side chain. So, so how this peptide like in cell synthesize like so what do we have over there like how does it start like what is it made up of? So these are my sugars. Good job. N and N stands for Okay. Okay. So these are monomers. Huh? And then they are rooted. They bonded together and so you this fibers and then the fibers might be cross so that's cross linking and which one is cross link like so it's not withh you are saying with mag with man and is there any cross between and so one is polymerization between and then the fibers those the adjacent fibers they might get cross the might this cross linking happens through sorry and and the enzyme is transfer transfer so this is the cross link Everything are transferred and this kind of like makes the the mesh that is made of the these polymers these polymer fibers. So this crossing makes us very strong. Yes. So so this is the last step transfer radation. Is that clear? Yes. So first is polymerization and then there's transparation cross linking and this is done through a enzyme called transparase which was also initially known as penicellin binding penicellin binding protein. So transpar when it was discovered like initially like when they saw that the the penicellin antivirus is binding something so they called penicellin binding protein and then later they discovered it is a an enzyme and then you will transcribe like this. So you will see this name pen binding protein PBP as well. So when a betum antibiotic with this betum when it binds to transep is enzyme. So that's the target. So for all the better what is the target the transep is enzyme. Okay. So you know the mode of all the antib and they enable the cross linking of of the so and hence they in limit the synthesis of a particular cell wall. Okay. So because of that what happens cell wall is weak. So when it's weak then the is fragile and things start leaking in and out. and and that compromises the integrity of the cell and then as in humans the cells will go to a process. So certainly are released from the cell wall which kill the cell. So these are theyidal. So these which are inhibiting cells they will be So you know the mode of action of all these things. Okay. So let's just read all penis differ from each other with regard to the side chain. Yeah. So and the side chain helps in in their determines the the antimicrobial spectrum because the side chain will determine uh whether they will be lipophilic whether they will be absorbed through G whether they will get into the cell whether they will be able to get into the ground negative ground because they need to get inside the cell binding the transports on the inside of the cell wall. Okay. So they need to get in the cell wall. So again the some may be able to get into the gum negatives better than g positive silver like thinner wall better than thicker wall others may not be able to get into g negative uh membrane so they will be more active against g positive. So again it it varies again so that that those properties are attributable to the side chain. So that gives you the antimicrobial spectrum. It gives them stability in the stomach and it also determines their susceptibility to betalcuctase. Now betalctomase enzyme will compromise or destroy the better ring. Nothing to do with cell chain but the cell chain if it's bulky it can kind of protect the better atom ring and the bet atom is may not be able to act on the better atom ring. Okay. So again, so because of the side chain, some antibiotics may become resistant to better while the other antibiotics may be sensitive to better. So when one antibiotic which is sensitive, we may not work on a bacteria producing better but then you have a different antibiotic which is a different side chain will be resistant to that and will be able to kill that behavior. Okay. So hence you have different spectrum. So you know about the cell wall and it's hetrodimeropolymer component of the cell wall pepidoglyen which is rigid mechanical gives you rigid mechanical stability and and um so you can chains and linear strands of alternating n and n as you said and they are cross linked by pepide chains. So we spoke about these things now. So this is the last step in the pepagon synthesis like this cross linking and it is inhibited by the better antibiotics including penicellin syphilos everything all of them are working on the same enzyme. So better bind to the active site of the transparis enzyme which is also known as peneline binding protein or pbp and that causes the peptides. Okay. So this electron irreversibly inhibit the enzyme transfer by days by reacting with the C residium once it's reversively inhibited. So obviously this synthesis of cell wall will be compromised. So immediately the growth of the vector cell is inhibited in the presence of betalactum license are also released causing the license of the material. We talked about this. So what gives the selective toxicity to these beta antibiotics and and and cell inhibitors because they target the bacteria. Yes. So we don't have cell wall. Huh? We don't have like we don't have cell wall. So so that's how they don't work on us like so they are not toxic to us. So this peptidon cell wall is unique to bacteria and no such substance is synthesized in higher animals. and and and practically they are very safe drugs. They are least toxic to there are obviously whenever you are giving a drug it will produce some side effects. It may have some other it might interact with something else. It might produce some uh effects. So with all antibiotics we have some adverse effects but they are not that among antibiotics. These are like the the most widely used this group and and uh and quite safe you know even during pregnancy as well like can safely be used during pregnancy not all of them but like some of them are are safe in pregnancy but like the better overall are are very safe and those antibodies which are safe they have over therapeutic index they have broad therapeutic So now about classification of penicellins. So we have natural penicellins like the the first peninsulin that was discovered like the very basic penis. So say so like we call benzile penin or they also called peng and and because they were the initial penins peninsulin. So they are effective against only they have quite narrow spectrum like they have effective as gram positive coxide anorobes and selective gram negative oxide but they are easily destroyed by betalctomases so they don't have like very wide spectrum like there are many bacteria which are resistant against these and then you have penicellin is resistant penicellines now again penicellin is and betalactin is an enzyme produced by bacteria which will destroy the beta ring and will make the antibiotic inactive okay or ineffective. So it will give resistance to the bacteria. Bacteria will be able to survive with that. Okay. So beta is but it's a group of enzymes. One of them is penicellinase. So penicellin is a betaase. So penicellin. So so again then then people started making antibiotics. So again the same structure basic structure but then they make few changes here and there like inside chain somewhere else. So so so they modify the structure a little bit so that and then they see if they are resistant against or they are they have better phocinetic properties or properties. So so again that's how they come up with different structures. So, so we have some pencil in these resistant pencils and and they can be used against stuff. Again, you are familiar with the step for you micro huh? So, yes. So, again some of the step may be sensitive to penance. Then there are other steps which are not sensitive. So they are better penisellin is producing step for. So then they are resistant to the natural penicellins for them we have this penicellin is resistant penicellins which can be used resistant oxide like fluoxyline dloxyline oxyeline. So these are effective against penicellin resistant steer like this stephox which are producing penicellin but these antibodies can are are resistant penicellin. So they can work on that step but then there are other stuff which are even more resistant which are resistant to almost all beta antibodies. So their mode of resistance different. So we call them math resistance step warrior MRA. Okay. So their mode of is different like the ones that we were talking about were like producing better. Those are better producing stuff for okay. But then there are other stuff for which modify their target. They modify the the pencil binding protein. Okay. So they are effectively resist to most of the uh the penicellin and beta antibodies. So we call them ma. So for them again we have different group of antibiotics. Okay. So here like these antibodies like nepsil oxyin can be used to penetrin resistance but not against msa then it will not work on msa. Okay. because MARSA has a modified uh target the binding protein is modified. So then you need an antibiotic which is not using that target something else. Okay. Or an antibiotic which can work on modified pen binding protein then it will work also. So then we have amino penicellins which are penicellin is sensitive but they have extended spectrum but not broadin but extended spectrum and that includes very commonly used emoxicin. Have you heard moxyline? You know and it's also part of a very commonly used antibiotic augment. Huh? Have you heard augment? Yes. It's very common antibiotic and very safe. So augment is is is a brand name the generic name is cooxoxic and cooxic is combination of and cleonic acid. What's the medication? We'll talk about that. And then you have anti-seudonal penicellins like these are penis sensitive but they work against. So they have like the spectrum as of penis plus they are active in sudonas like pepper. Now what do you know about sudonas? Is it ground positive or g negative? G negative. G negative. Huh? It's a ground negative. Then why we are melting differently? Like if if the amount of persons working were working against G negative. So then why we need an anti-seudon? Because again the structure of pseudomonas you know is slightly different. The this gram negative but the outer membrane is very less permeable compared to other gram negatives. It's probably the form are there through which the antibodies go in the outer. So, so it's like very like it's less permeable antibodies. So, only few antibodies work on sudonus like the other antibodies like which are working may not work on sudonus. There are only few which are able to work on sudonus and that's why we usually mention sudonus separately that okay this individual works on sudonus. So, because we don't have many options against so like there's a separate group which is effective against sudamona. So we call them anticodonal penicellins. Phocinetics again penicellins are excretion can happen through kidney via secretion through tubules. Tubular secretion like with the other organic acids like organic acids are secreted from there. So it can be inhibited by some other drug like proenacid. So it blocks this like I don't know if you've done gout or no. Yeah. So so for gout like you can use propen. to inhibit the secretion of uric acid. So here the probenacid can inhibit the secretion of penicellins. So it will elevate the levels of penicellins in your system. So again if you use a very low dose it should be effective with proparet and peninsulence cross placal barrier but none has been shown to be territogenic. Okay. So they so they are quite safe. Penicellins have and patients with impaired function may need some dose adjustment and the nin oxyin are exceptional because they are primary metabol liver. So they don't need dose adjustment with renowns sufficiency and benzene penicellin is a deeper form. So it says a longer half life. So again so again the dozing interval like you can use once a month dose type of thing. So where you have need electronic dosing for some prophylactic purposes clinical uses again it's difficult at this stage because again it's you need to know the in any given infection you need to know which pathogens causing their infection only there you can determine so again it will be very early for you to go into clinical uses if there's some very particular particular clinical use then we'll talk about that otherwise at this stage avoid but hopefully on the next block we'll go into more details of that like when you speak of specific diseases then we'll go into that but like then if there's something specific situation then here we'll more focus on spectrum but if there's if like if if there's a drug which is specifically used for osteomalitis because of good bone penetration so then yes we'll talk about that adverse effects again the more common are hyper sensitivity reactions and that can go on like it's a wide spectrum of hypersensitive reactions and it can be mild rash to analactic shock so it's a spectrum and uh quite common it can go up to 10%. And the cross allergy sensitivity is there among penicellins. So if a patient is allergic to one penis it will be he will be allergic that she will be allergic to all other penicellins. And then there are few other side effects. A mechanism resistance as we just spoke that the antibiotic has to reach at this site of action in the active form and it needs to bind its target. So target has to be there. So when we speak the the penicellin resistance so there's a natural resistance like some bacteria don't have cell wall can you give me the name so if you use peneline like this microplasma will it work no so that's called natural resistance huh but then there's acquired resistance which like they acquire like they like resistance to penis and other betalactins is due to one of the three general mechanisms and those are inactivation of the antibbody by betalacttomy. So the bacteria starts producing betalacttomase and inactivates the antibbody. So that's one mechanism. The other is modifying the target like the penal binding protein. This is what ma does. So it modifies the pencil binding protein and then impaired penetration of the drug to the target paling protein. So again uh sometimes that can also happen but it's not very common mechanism. So again like the we talked about structure. So this is the site of penis action but it is a side chain which can confirm sometimes the protection to this uh access to this activation this site where penicellin would work. So hence it can give it the the protection against penicellinasis. Now we have certain betalacttois inhibitors. So there are drugs which on their own they don't have antibacterial activity but they can inhibit the betaise enzyme. So you can combine with an antibiotic or penicellin antibiotic or betalact antibiotic which is sensitive to betaise but then is combined with betalacttoase inhibitor. So that inhibitor will inhibit the vector in the bacteria then that antibiotic will be able to do its work. So and the example is like as you said like augment. So augment is oroxic combination of amoxic and cleanic acid. So one of the better is cleanic acid is very commonly used especially in koxic then you sell vectum tesum there others as well. So, so they reversible inhibitors of metalises like amoxicin plusic acid makes it which is like the marketed as one of like one of the drug market is augmented like one of the brand names is augmented but then there are many other local brands these days and then you have emperin plus and and then the combination uh one brand name is unisonin. Then you prepar which is used with tzobacttor. We also call pept like in clinic you call pipes and again one drug is like one brand name is zosin. Okay. Now syphilosporans. So this is another class of betalactive antibiotics syphilosporins and it is subdivided into five generations. So your first, second, third, fourth and fifth generation. Now as you go from first to second and third and fourth you see initially it has more ground positive coverage and then it is having more and more ground negative coverage and less ground positive and the problem towards the fourth again more ground positive and negative both. So if you look at the first generation and the two examples would be cphilaxin and cphazol. So it's it's covering gram positive oxide and some ground negative bacteria like ecoli proteins. Have you been exposed to these names? No. The bacteria. No. So hopefully in the coming weeks you will you will be like taugh about talked about these criteria and you'll be familiar with these. So these are ground negative eolite they are ground negative material and so some ground positive ox and some ground negative material but mainly against ground positive. So first generation is more against ground positives. Then when you go to second generation like facoxin so you have increased ground negative coverage but as well as also ground positive like hemopin influenza not as effective as gram positive as first generation. G first generation is more effective as gram positive. Second generation has more coverage for blood including hemophilus influenza. So hemophilus influenza was not there in the first generation. So whenever you suspect hemophilus influa you go with the second generation. Then third generation like septra septine and then if you want to know about oral so there's sephine which is oral agent like other third fourth generation are mostly paral the names. There's like there's now like there's in third generation there's a suffix which is oral. So the third generation is both gram positive and g negative oxide like n gonora and many other gram negative rods and among these there are different drugs than each generation we have named only two or one in each class but there are many. So like in third generation this drug called septadine which covers pseudomonus. So other third generation sephus pollins don't cover sudomonus only sephidine cover sudonus. Okay. And then you see which is comparable to third generation but more resistant to betalacttoises and has a greater activity in ground positive and sudonus. Then you go to fifth generation where it's again comparable to fourth generation but more activity against gram positive and msa but no activity against duma. So fifth generation doesn't work against so for pseudomonas and single sponsors you have either fourth generation and third generation septacity okay but only the fifth generation works in versa. So we said betrons don't like working in msa because they have modified the penicellin binding protein but fifth generation somehow is able to work on the modified version of the pen binding protein or transpire because they made a new drug which is able to bind the modified version. So it is effective as muscle. Now the other like we said like in there are penisellins there on there are carbopen carbopen I'll give you names I might reduce like in final list I'll reduce some of the names okay so there is imipenum which is always used with celestatin we'll talk about so imipen muropenum penum dorip penum so again the names are easy carbopen so this everything is penum penum penum in the end okay so imip penum Again it's always coated with the slat. It's an inhibitor of renal dehydropepase enzyme. So renal dehydropase hydraysis the imipen so it will reduce the concentration very quickly. So that means the half life will go down and you need to very frequent dosing. But if you give it statin which will inhibit the signal dehydroeptide enzyme then the halfife of the imipen will increase and then probably you'll need less frequent dosing. Okay. And it is active against most clinically important bacteria including nerops like this is a very broad spectrum and it's not destroyed by most vitaltomises and it is important for inhos empirical agent for life-threatening infection. So again it's a very broad spectrum. So in we use in CS infections are when we suspecting like a resistant bacteria especially when we acquire an infection in the hospital it's likely to be resistant to many antibiotics because when it's in the hospital that means that bacteria that somebody acquired in the hospital that patient from where it came would already be exposed to some antibiotics. So so the bacteria which are roaming around in the hospital from patient to patient moving around they are likely to be resistant to many antibodies. So we also use the term nocomial infections. So no is something that you acquire from hospital. So again for those infections you need antibiotics which have broad spectrum which can work against resistant bacteria. It's administered IV and it has like it can cause filibitis which is inflammation of the vein where it's injected and and it can cause nausea, vomiting or seizures. Monobactum like there's only one drug that is relevant here as trul and it's primarily and active against aerobic gram negative organisms and and it's used in in severe sepsis often hospital especially infections of respiratory tract GI tract and femal tract again it's effective against gram negative arobs okay so gram negative arobs are very common in in infections which lead to sepsis in patients especially UTI and these things again because of narrow spectrum you don't use it alone or like once you have estron usually is used in the hospitals after the sensitive reports or like in special situations when it's resistant to others then they go with the estron so the question is why better like better is essential for antibacterial activity of the group then and which is there in all the panic symphones and others then why micro bacterial or antimicrobial spectrum is different. Yeah. Because of the side chain, their properties change. Huh. Like if if they if they become hypopilic, they'll be able to cross the bloodb brain barrier. Okay. So so those will be effective against menitis. If because of side chain if they become very big, they may not be able to get into the thick cell wall of ground positives. uh there may be some so so chain might make it more resistant to better activises. So so so because of the side chain properties mainly u so so so their properties how they get absorbed and how they reach the target how they encounter these other enzymes. So so they that will change the spectrum. Now this is the last drug that we need to do. So we were talking about the betalactic antibiotics and the other cellosynthesis inhibitor is non-metal antibiotic which is glyopet and which is one drug that we need to talk about is venkcomy quite commonly used especially serious infections. So venkcomy inhibits cell work synthesis by inhibiting the peptide polymerization and you know the polymerization happens before the cross linking first polymerization and then the cross linking cross linking is the last step. So it's inhibiting gas step which is before the inhibition of the beta electron. So beta electron antibodies are working at a later stage or final stage of silver synthesis which is the syninking pencomy is acting step earlier which is polymerization of the peptide when the polyeptides are. So when the monomers are polymerized so venkcomy inhibits cell vector cell synthesis by inhibiting pepidogen polymerization and if it's mainly the main claim to fame is it's effective against msa vencom is not absorbed from the gut so it is used IV but then there are like this one indication where you give oral Remember yesterday I said like sometimes you might use such medications which are not absorbed from the gut but sometimes you might give oral when you need that topical effect in the gut. So when the pseudo pseudommebrinous politis caused by C defic we talked about super infection last time huh? So now because the c deficil is producing toxins and the toxins are causing the the colitis and colitis. So you need to kill the uh seed deficil present in the gut lumin. So and and vencomin can do that. So venkcomy is very active against ced deficil and because you need its effect in in the gut lumin. So you can give it orally you don't need absorption. So in that situation it can be given orally otherwise it is used and it can cause as hearing loss venus thrombosis and there's something called dreadman syndrome that can happen due to cytoine release following rapid inter mis administration and some hypersensitivity and ephrotoxicity.