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Protein synthesis and membrane inhibitors TR AM 032117

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So we finished up with talking about the cell wall inhibitors in the next topic on the agenda are the inhibitors of the protein synthesis so there are several major fought six major classes five of them are present over there okay so we have two drugs that inhibit 30s subunit and here three drugs are illustrated but there’s a little bit more just for different

Types of drugs that inhibit 50s okay so 30 aminoglycosides remember bless you remember we talked about zelman waxman how he discovered aminoglycosides tin amaizing neomycin streptomycin turns out when they bind the 30s subunit see illustrated right here they change the shape of the 30s which doesn’t prevent protein from being synthesized the protein that is made is

Incorrect so those incorrectly produce proteins with the wrong sequence essentially when they they break down the match between the coat on and in thai column so say instead of syrian there will be at no.3 i need inserted and stuff like that so those mismatched proteins then can be transported to the membrane can stop performing different functions so they screw

Up the cell big time okay and that was pretty much the first broad spectrum antibiotics right tetracyclines that were discovered later are considered to be maybe the the antibiotics with probably the largest spectra they can be used to treat virtually any type of microbe gram-positive gram-negative obligate intracellular parasites spiral kits all of them can be

Treated with tetracycline of course you know that slightly different level of success but tetracyclines are used for pretty much all microbial infections they prevent trna from binding to the 30s subunit essentially stopping the protein synthesis right so tetracyclines and aminoglycosides broad range antibiotics that bind to the 30s subunit what about others so

Micro lites prevent the ribosome from translocating moving down the mrna that make sense they bind to the 50s so ribosome cannot move down the mrna cannot read the mrna through and protein synthesis is stopped they also static a broad spectrum into antibiotics that you may have seen very popular with rome ison and az throw meissen that makes sense now lin cosa

Mites lincomycin in its relative clindamycin modified version so little cosa mites also inhibit the formation of the bond between the growing the growing chain of the growing peptide chain and the new incoming amino acid s does chloramphenicol okay so chloramphenicol is effective inhibitor broad-spectrum inhibitor of the trance not trance the peptidyl transferase

Activity essentially it prevents the again the bone formation between the amino acid and the growing polypeptide chain right the last the the newest of that group of protein synthesis inhibitors is linezolid that belongs to the group of drugs called excessively dino’s people to blame for such names are chemists okay that’s where it comes from organic chemistry

Okay excessively the known is surprisingly a rather small molecule why focus so much on linezolid because linezolid doesn’t only have the broad spectrum of activity there’s a quite an effective drug against the mycobacterium tuberculosis you will you will see a lot of time that i would say something this drug works well against gram positives this drug works well

Against gram-positive and gram-negative and this drug works well against tb because mycobacterium is notoriously hard to treat we i don’t think we talk that much it hides inside macrophages and that’s one of the reasons okay now linezolid is unique because when it binds to the 50s subunit of the ribosome it actually prevents the ribosome from assembly so protein

Synthesis doesn’t even start that make sense this antimicrobial have probably are the most used now in a clinical practice because they have such a broad range they have fairly low levels of side effects because they have high specific toxicity okay and a lot of them were discovered recently so resistance to them is maintained relatively low does that make sense

Although well i must say some of them like excessively denotes like linezolid when as elite is considered to be a supplement drug which means it shouldn’t be used as the primary drug for treating any infection only if other drugs fail to treat the infection linezolid should be used that steel allows to maintain the resistance levels to this drug a deferral alone now

This guy’s yes that’s a great question why first of all i think you have will have problems reaching the concentration sufficient enough to treat second mycobacterium does not is not present as the free crowing bacterium on the surface in the alveoli of the lungs it is inside of macrophages and the drug essentially has to be delivered into the macrophage another

Thing with mycobacterium as with pretty much any drug it’s easier to treat actively replicating microbe do you understand why when micro replicates it performs a lot of biochemical processes performs activity it synthesizes cell wall it produces protein you have something to inhibit if microbe does not reproduce if it’s in a latent stage or an active stage or gold

Whatever you want you cannot treat it you cannot treat endospore that’s another problem with mycobacterium if mycobacterium doesn’t replicate and it replicates extremely slow okay it’s really hard to treat so i think the reason so iv injections of the drug for mycobacterium should be more effective considering the circulatory network around the alveoli those drugs

Should diffuse fairly easily towards the site and since mycobacterium tends to go in in acute cases it can be extra pulmonary so they can be neurotropic osteo tropic that may also contribute you know but inhalation one of the major concerns with any type of inhalation drugs concentration like with the vaccine that you probably have heard the flu mist one of the

Concerns about flu mist is that the amount that is delivered which spray is not what’s the word but not the word reliable not standard okay it varies greatly so that’s that’s probably the reason cancer what did i just do i wanted to just few words about the membranes i love this drugs it’s like nukes okay really because they kill everything polymyxin polymyxin b

Polymyxin e there worked really well against gram negatives which is not very common they work against multi-drug resistant mdr multi-drug resistant microbes okay daptomycin is also good against gram-positive mostly but also against multidrug-resistant it picture this picture actually shows you how polymyxin e or koala seen binds to the to the membrane okay and

Disrupts its structure essentially polymyxin just makes slick membrane and stable but as they can do it to the bacterial membrane you can do the same to the you are adequately polymyxin on notoriously toxic they are not used for other than topical treatment you can see polymyxin b tropical wound infections right ah polymyxin e bowel the contamination so it means

That it’s going to sweep through the bowels killing everything there the patient has nothing to lose at this point okay systemic multi drug-resistant infections so we talk about systemic infection with i don’t know multidrug-resistant tb okay multi drug-resistant gram negatives it’s colistin is is really powerful it has very high level of nephrotoxicity in in the

Long run it will lead to the kidney failure and it was for a long time last resort in terms of the treatment really lost hope well guess what there’s a plasmid that confers colistin resistance and it now starts to spread among all the bacteria in the world was recently found in the bacteria in the united states so it’s here it’s going to happen okay daptomycin is

A very interesting antimicrobial i i i’m not going to ask you about the little intricate details but what it does is absolutely amazing so it’s a lipopeptides it’s a part lipid part peptide and it’s lipid part incorporates itself into the membrane and it’s not one molecules many daptomycin molecules peptide parts organized in the poor the channel and that channel

Allows the flux of ions across the membrane bless you so what happens cell becomes depolarized hyperpolarized whatever its membrane potential changes and it screws up sal veta so it’s pretty amazing mechanism though it works not only on bacteria but in humans as well so that’s why you know book theory may cause by marissa sounds almost like a death penalty okay so

You have to have to think about what it targets if it targets membrane if it targets the membrane then it’s going to be pretty toxic these membranes have a common structure that make sense good okay

Transcribed from video
Protein synthesis and membrane inhibitors TR AM 032117 By Mikhail Khoretonenko