Fluoroquinolones: Mechanisms of Action and Resistance
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- Опубликовано: 28 мар 2011
- Developed and produced by www.MechanismsinMedicine.com
Animation Description: In this animation, we demonstrate the biology of DNA replication leading to bacterial cell division in a gram positive bacterium, such as S. pneumoniae.
The DNA is shown as a circular double strand within the bacterial cell. Like the DNA of all living organisms, it contains the unique genetic code for all of the proteins required for bacterial survival. Bacteria replicate by a process known as binary fission whereby one bacterium separates into 2 new daughter cells. However, before this can occur, the bacterium must make an identical copy of its complete circular DNA.
DNA replication requires that the two strands of DNA separate so that the genetic code of the bacterium can be read and a new complimentary strand can be created for each of the original strands. To accomplish this, various enzymes known as helicases break the hydrogen bonds between the bases in the two DNA strands, unwind the strands from each other, and stabilize the exposed single strands, preventing them from joining back together.
The points at which the two strands of DNA separate to allow replication of DNA are known as replication forks.
The enzymes DNA polymerase then move along each strand of DNA, behind each replication fork synthesizing new DNA strands (in red) complementary to the original ones.
As the replication forks move forward, positive superhelical twists in the DNA begin to accumulate ahead of them. In order for DNA replication to continue, these superhelical twists must be removed.
The bacterial enzyme, DNA gyrase, which is also known as topoisomerase II, is responsible for removing the positive superhelical twists so that DNA replications can procede. DNA gyrase is an essential bacterial enzyme composed of two A and two B subunits which are products of the gyrA and gyrB genes. This enzyme has other important functions which affect the initiation of DNA replication and transcription of many genes.
With the combined involvement of these enzymes, an entire duplicate copy of the bacterial genome is produced as the 2 replication forks move in opposite directions around the circular DNA genome.
Eventually, as the 2 replication forks meet, 2 new complete chromosomes have been made, each consisting of 1 old and 1 new strand of DNA. This is referred to as semi-conservative replication.
In order to allow the 2 new interlinked chromosomes to come apart, another bacterial enzyme is needed which is known as topoisomerase IV. This enzyme is structurally related to DNA gyrase and is coded for by the parC and parE genes.
Topoisomerase IV allows for the 2 new inter-linked chromosomes to separate so that they can be segregated into 2 new daughter bacterial cells.
Complete separation of bacterial cells
Fluoroquinolones. First mechanism of action -- inhibition of DNA gyrase.
Fluoroquinolones act by inhibiting the activity of both the DNA gyrase and the topoisomerase IV enzymes. For most gram negative bacteria, DNA gyrase is the primary fluoroquinolone target. Fluoroquinolones have been shown to bind specifically to the complex of DNA gyrase and DNA rather than to DNA gyrase alone.
As a result of this binding, quinolones appear to stabilize the enzyme-DNA complexes which in turn results in breaks in the DNA that are fatal to the bacterium.
A second mechanism of fluoroquinolone action is shown here. With some exceptions, topoisomerase IV is the primary target of fluoroquinolone action in most gram positive bacteria such as Staphylococci and Streptococci, with DNA gyrase being a secondary target.
The separation of 2 new interlinked daughter strands of circular DNA is disrupted.
The final result on the bacteria, however, is the same. Bacterial replication is disrupted and the bacterium breaks apart.
The relative potency of different fluoroquinolone antibiotics (and thus their spectrum of activity) is dependent in part on their affinity for either DNA gyrase or topoisomerase IV or both.
One of the most common mechanisms by which bacteria acquire resistance to fluoroquinolones is by spontaneously occurring mutations in chromosomal genes that alter the target enzymes -- DNA gyrase and topoisomerase IV or both. The frequency with which these spontaneous mutations occurs may be in the range of 10-6. The effect of mutations on the activity of an individual fluoroquinolone will vary depending on the number of mutations, the location of the mutations and which target enzyme is affected.
If a mutation occurs (either in the gyrA or gyrB gene) that alters DNA gyrase and results in a reduced affinity of the fluoroquinolone antibiotic for this enzyme, the organism will become resistant.
View animation to read more.
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I was prescribed Cipro in 2014 for an infected tooth. Within a month I had sever pain in my rotator cuff and had a series of steroid injections (which unfortunately accelerates the effect of Fluoroquinolone induced tendon rupture). I had surgery in 2015 and my surgeon said the tendon was paper thin with no apparent cause. After nearly a year of painful physical therapy I saw an article on damaging effects of Cipro and all the pieces fell together. My surgeon later confirmed that there is a good chance Cipro was the catalyst. Sadly my other shoulder needs surgery but I can't bring myself to do it. I've played violin since 1974 and external rotation is critical on my fingering hand.
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What is left out of this informative presentation is that topoisomerase inhibitors also work on the cells of mammals, including us, not just the cells in bacteria, creating all sorts of bad effects up to and including death. Topoisomerase inhibitors are commonly used as chemotherapy for cancer patients and "late effects" (for both chemotherapy and fluoroquinolone antibiotics) may show up years or even decades later. There is a high rate of failure to connect the new problems to the guilty medications (i.e. Cipro, Levaquin, Avalox, Tequin, etc.), but the FDA now admits that permanent and progressive peripheral neuropathy is one such effect from taking fluoroquinolone antibiotics and includes a black box warning that fluoroquinolone antibiotics are not to be taken except as a last ditch effort to save a life. It should also be noted that Gulf War disease is a reaction to everyone taking Cipro.
It's interesting this is taught in med school but fluoroquinolones attacking human eukaryotes and mitochondrial DNA isn't taught. Why do you think FQs don't attack human cells too, both of which have forms of topoisomerase? Hint: they do
My understanding is that the DNA of mitochondria more closely resembles the DNA of bacteria and not the cell DNA.
i'm a medical student, and i just wanted to say - these are great!
an on point explanation LITERALLLY AMAZING JOB
@moadpt thank you. Your opinion as a physician is particularly valuable.
Only problem is that it does it to your own healthy body cells and mitochondria as well causing extreme side effects in some people like spontaneous tendon ruptures and even suicidal thoughts. Should be last resort...
Thank you very much ! Very informative video with crystal clear explanation and animation . Keep up the great work . Any video on plasmid mediated efflux pump of fluroquinolone resistance ? take care and stay blessed :)
Loved this video, thank you!
AMAZINGGG!!!! more like these would make life so much easier!!!
I suppose you've never been on fluroquinolenes... Please watch reviews of patients taking fluroquinolenes... Some have never been able to walk again... And if ever someday you're prescribed any kind of fluroquinolene, reconsider all of your choices before taking... I call them poison pills
It is very useful and comprehensive. It explains a lot for selectivity and specificity of action for different floroqunolones may be need a little bed on efflux as a mechanism of resistance .
Finally it will distroy your ear eyes and center nerves system
thank you!! it makes understanding pharmacology such a breeze
thank you, I was confused on how topoisomerase II works
Very quick, simple and easy to understand. Thank you.
Wonderfully clarifying animations and explication, thank you :)
Conciso, preciso e interactivo, muy buen vídeo.
i'm an instructor of pharmacology your videos very useful for me and my students thank you.
@laex114 Most of the narrative text is provided in the "Animation Description" section (click on "Show more" link under the video to expand)
Amazing explanation with animational vidio , it clearified all my difficulties regarding this..
Thank you so much, Sir..!!
So clear voice, thank you
this is the best youtube channel ...makes things super easy
Wonderful work. I like the subject.
@MechanismsMedicine thanks a lot! very well understandable videos
greets from germany :)
Great work , thanks alot
amazing video...thanks a lot!
Awesome animation and a very good demonstration.
This video is really accurate and in point and very clear
thanku so much ... thanks for sharing ... awsome video
perfect thanks a lot ♥
Very clear and interesting presentation
these videos are really helpful.........keep upoading such videos...thanx
Best video ever . it was complete .
Very nice video. Really helped me understand how Fluoroquinolones work. I am a second year pharmacy student and was referred to this video by my Pharmacotherapy professor during our Infectious Disease module.
where did you download these videos from? is it an interactive program? you would help me a lot by telling me :S
Great video, thank you.
thanks great stuff
Brilliantly explained
Does this antibiotic cause peripheral neuropathy? People are saying it does and this scares me. I have taken this antibiotic two times in my life and I have a neuropathy!? Help!
Maye McDonald Yes it does.
Maye McDonald No, only polymyxines-like antibiotics are toxic for the nerves. But those are rarely used on patiënts (only as a last resort)
Ordon Yes they do cause peripheral neuropathy (and a ton of other crippling side effects including fluoroquinolone induced tendinopathy, depression, suicidal thoughts, muscle atrophy, etc etc...very nasty stuff). Educate yourself before trying to educate others.
Fluoroquinolones cause peripheral neuropathy:
www.fda.gov/Drugs/DrugSafety/ucm365050.htm
Lucky me, I already have polineuropathy cuz of diabetes :-)
muaythai193 The doctor and the pharmacy said that doxycycline might work. But E coli is a very tricky bug. NO, I will not take another Zpak because it destroyed my left hip even 6 months after I stopped it. I also gave me constant heart palpatations and I vomit about 30 times a day. But an E coli infection in the tongue can be deadly and cause bacteremia. And I also have two artificial hips that can be infected from bacteria. Since they are titanium hips, any bacteria that reaches them will be eradicated ONLY with IV vancomycin for 6 weeks. And if it doesn't work, they will do a girdlestone. So I am extremely upset, worried and depressed right now. Just how much more miserable can I get? I already can't walk, I vomit all days and every minute I will get 3 or more missed heart beats! I throw up even looking at food.
thanks for the video. ☺️
Best explanation ever
FANTASTIC VIDEO
Excellent thank you
merci 😊
j'ai une question : Lorsqu'une mutation se produit, le rôle de l'enzyme reste le même malgré le changement de structure ؟؟!!!!
Thanks a lot for this explanation 💗
Thank you very much!
very good presentation.
Nice video keep this continues
Studying drugs is not difficult - if you are interested in them.
Anyone know how the the fluorine in the fluoroquinolones specifically reacts with the type II topoisomerases to effectively stabilize them, stop transcription/translation, and produce the desired antibacterial effect?
Andrew028 I would like to know this too. I have read that Dr Mark Noble compared Fluoroquinolones to fluorouracil, the chemotherapy drug, which is reported to metabolise to the highly toxic metabolite fluorocitrate, inhibiting the citric acid cycle.
Waoo... It so good...
Made many of mine concept clear..
Thanks a lot 😉😉
thank you
very good lecture
thank you :)
@MechanismsMedicine oooh...thanks... haven't noticed
good lecture.could have been more beneficial if function of subunit A and B of DNA Gyrase like nicing and resealing and introduction of negative supercoils also eplained
This is a smartly produced video that explains how this class of drugs work, thank you for posting.
Thank you
"for me, the greater picture of the bacteria not being able to survive amongst the new environment you're creating is still more understandable"
Very clear
excellent vedio
thanks
Wonderful
i love this video
and this is why these are the most dangerous antibiotics in the world. so many suffer from using these drugs
So helpfull video
Mechanisms in Medicine Inc., developed these animations for an educational CD-ROM "Understanding Bacterial Resistance in the Community Setting: Clinical Challenges to Antimicrobial Therapy".
tyvm
Thankyou
research colostrum 6 by immune tree..levaquin ruined my life 3 yrs ago..this is healing me !!!!
What is the reasons of mutation sir ??
thankuh sir
Topoisomerase IV is in bacterias and topoisomerase II is in mammals..
Can anyone write what the guy says?... please.. i'm learning english and can't understand what he says... he speaks too fast for me... PLEASE
I remamber my teacher showing us this 🌚
Learn daily a drug with me @ drug of the day
i love it when the cell explodes lol
@Floxiemoxie1 Yeah, if you're a bacterium...
Thank you here me searching for it
👍
Humans have DNA gyrases (topoisomerase II) and other topoisomerases. Fluoroquinolones have 1000x affinity for bacterial forms of DNA gyrase than they do for human forms, so you should not be concerned with this class of drugs affecting your DNA if you are using it to treat such organisms.
-Doctor of Pharmacy Student
+Barbara Parker Madam, read my side effects above. I stopped taking this med over 5 weeks ago, and I am still getting all of them with new ones almost everyday. The doctor, who was skeptical at first, now believes me. He said I am the sickest healthy patient he has.
He was shocked when I could not step up to the exam bed without help. My legs would not allow me to. And I am so out of balance that I have to use either a walker or a cane or i may fall. I almost fell several times in my own apartment already.
The neuropathy is getting better, but there are days when I can not feel my toes. And then there are mornings when I feel like a thousand hot needles are trying to pierce my arms.
You SHOULD BE VERY CONCERNED. These are devastating and destructive and disabling.