How do antibiotics kill such a wide variety of bacteria?

[hitmankratos]

An Antibiotic can kill many diffrent bacteria...How can it do that? Shouldn't it be "programmed" to attack only one sort of bacteria?

[NeonBlack]

I think I remember from my freshman biology that some antibiotics work by breaking the cell wall or by disrupting the Krebb's cycle, which is common to all organisms.

I'm sure wikipedia has a lot more information on the mechanisms.

[ecoli]

Lots of antibiotics work by inhibiting protein synthesis. Bacteria and humans use different types of ribosomes, so you can kill pathogens by stopping their protein translation machinery. However, lots of times, this will kill the good bacteria as well.

[doctor_plague]

It's exist a lot of types mechanisms of antibiotic action. In addition it's need remember about that some biological process are common in different bacterial species.

Excellent example is cell wall syntesis inhibition by penicillines. (or, as ecoli said, proteins syntesis ingibition by aminoglycosides)

P.S. sorry for my poor english...

[big314mp]

An Antibiotic can kill many diffrent bacteria...How can it do that? Shouldn't it be "programmed" to attack only one sort of bacteria?

 

This effect sort of exists. Example:

 

Polymyxin B attacks cell membranes. However, it is only active against gram-negative bacteria. Gram-positive bacteria have cell walls that are too thick for the Polymyxin B to get to the membrane.

 

http://en.wikipedia.org/wiki/Polymyxin_b

[CharonY]

Shouldn't it be "programmed" to attack only one sort of bacteria?

 

Why "should" it? Bacteriocins, however, are interesting antibacterial agents in that regard. They only kill off closely related bacteria (not carrying the required resistance genes). With that those that possess the bacteriocin and resistance genes kill off specifically those that are similar to themselves (and hence are likely competition in the same ecological niche).

[Fortissimo]

Dont they just inhibit enzymes? take for example, the flox drugs, Cipro, levo etc. they inhibit dna gyrase which stops bax from multiplying. most bacteria have similar enzymes i guess.

[CharonY]

The majority of all natural occuring antibiotics target proteinbiosynthesis or, more precisely, the ribosome complex for obvious reasons.

There are, as mentioned, other targets, though they are generally not that abundant.

[profescher]

Antibiotics work by attacking or preventing key processes: Penicillins and vancomycin act on cell walls, without which bacteria die. Macrolides, erythromycin, tetracyclines and aminoglycosides, prevent the organism synthesizing essential protiens. Sulphonamides inhibit folic acid synthesis which bacteria have to make in order to make DNA, we get it from our diets and so get few side effects from the drug. Quinolones, imidazoles and rifamycin inhibit or damages DNA. Polymixins disrupt or damage cell membranes and drugs like amantadine prevent reverse transcriptase.

 

All antibiotics have initially been derived from natural sources, plant rotten vegetable matter, or other bacteria that have evolved to secrete them as a survival mechanism, when competing with other bacteria. As such it is not fully understood how all of them work, just that they do. Some like the penicillin family have later been tinkered with in response to drug resistance.

 

I can explain this better send me a message if you need clarification or if i did not fully answer your question, like why they do not target such and such specifically, but right now i have to do dinner.

 

PS charonY i think you are quite incorrect on that note, i can quote my sources all of which are reliable, what are your sources so i can compare them with my own?

[CharonY]

My source? A colleague across the floor. He worked on antibiotic resistance proliferation by mobile genetic elements. We used to lunch together. As a side note, the single largest groups of antibiotics (even including the synthetic ones) that you mentioned act on the ribosome complex.

 

On yet a slightly different side note, just acting on my memory, I seem to recall that rifamycin actually inhibits transcription (and do not act on the DNA or DNA replication machinery), imidazole antibiotics do not act on DNA either, IIRC they are mostly used as antifungal compounds inhibiting e.g. sterol synthesis. There are antibacterial derivatives but again they inhibit enzymes on some kind of prosthetic groups, I think. I would assume hemes would be prime targets. In any case it is not the imidazole ring alone that acts antimicrobial.

And, as you actually mentioned (possibly unknowingly?) amantadine is not an antibiotic but an antiviral compound.

[profescher]

CharonY, I did not mean to offend you and apologize if i did. However it seemed to me there are a wealth of other targets that other antibiotics use, including new targets currently being investigated and that they merited mentioning.

 

Concerning rifamycin i am ever so pedantic for the details, so i checked the Oxford Handbook Of Medical Sciences (2006) p789 says its target of inhibition is DNA synthesis via DNA-dependant RNA polymerase. And I said "Antibiotics work by attacking or preventing key processes" and the transcription of DNA is a key process, perhaps then we are both right as I did not suggest it worked in DNA or DNA replication machinery but that "Quinolones, imidazoles and rifamycin inhibit or damages DNA" and rifamycin certaily inhibits DNA synthesis. Correct me if I am wrong.

 

According to the same source Imidazoles inhibit DNA synthesis by generating reactive intermediaries that damage DNA. According to the aac apart from thier antifungal properties they are active against gram positive bacteria and according to the Oxford Handbook Of Medical Sciences they are also active against anaerobes. However different imidazoles can act slightly differently, perhaps we are each more familiar with diiferent types.

 

Yes i mentioned an antiviral and yes we can label them all anti-fungal, antibiotic, anti-viral. But just as often they are grouped together under the single heading of antibiotics dictionaries would confirm this. My aim was to give a broad picture of the different actions of antibiotics and to get across in not too many words that they target not sprecific bacteria, but specific components of bacteria such as cell walls, or key processes that bacteria need for life such as DNA synthesis. But as i said i did not mean to offend you.

[CharonY]

I was not offended, I just felt I had to correct some misinformation. kind of a pastime of mine. I am not sure what precisely is written in the handbook but from what you quote:

ts target of inhibition is DNA synthesis via DNA-dependant RNA polymerase

it is abundantly clear that transcription is targeted. the DNA-dependent RNA polymerase synthesizes RNA, not DNA. As such the DNA synthesis itself is not the direct target.

 

Imidazoles are varied cyclic compounds and are no antibiotics per se. For instance, histidine also contains an imidazole group. Thus one cannot describe the group of imidazoles as antibiotics.

 

Finally, traditionally antibiotics are only used to describe compounds that kill exclusively prokaryotes. That is the reason why one often remarks that antibiotics do not effect eukaryotes. However, a more lenient (but usually not encouraged) use is to add antifungal compounds to the mix. The reason is that many also describe fungi as microbes. But in my opinion this should be avoided and the distinction between eu-and prokaryotes should not be blurred too much.

In any case, antiviral activities are on a completely different note, as viruses are generally not recognized as microbes or living organisms. As such antiviral compounds are not called antibiotics.

 

Hope that clears it up. Again, I am not offended, but as I am generally shooting my posts off the hip between two sips of coffee I often type things rather condensed as they appear in my mind. It may read like that sometimes.

[profescher]

I was pleased to hear from you again and thanks for not being offended, that s the last thing i wanted to do being new here! I am in fact tickled to have people to debate with. But I do not think it was misinformation and just cannot help myself i have to go over it again.

 

I will hit the books later, i have to get to the bottom of this, you obvioulsy know what you're talking about, i covered this in a research piece on drug resistance a while back and i set great store in my books and cannot imagine they are wrong either. I think the answer is along the lines of the following (But i will check later!) ... To synthesize DNA the cell must have an RNA copy and then synthesize the DNA using reverse transcriptase. If the production of RNA is inhibited so must the synthesis of DNA.

 

I will also get back to you on imidazoles (I'm just about to go out.) Technically yes it is good to have the different groupings for clarity and anti-virals are less often grouped under that heading than the others because they are generally not considered as living organisms, however i am sure that thier inclusion is due to some similar mechanisms in anti viral drugs, but i'm out of time have to finish this later

[CharonY]

To synthesize DNA the cell must have an RNA copy and then synthesize the DNA using reverse transcriptase. If the production of RNA is inhibited so must the synthesis of DNA.

 

Meep, wrong. Reverse transcribing RNA to DNA is a purely viral phenomenon. Bacteria do not do this (refer to the dogma of molecular biology for details). It seems to me that you are also confusing transcription with replication.

 

Again, as viruses to not have a metabolism anything targeting them (afaik there is not a whole lot of it, either) are fundamentally different to anything targeting bacteria (let alone fungi).

 

I would recommend you to check the definitions once more. To me it seems that you are confusing a number of aspects and probably definitions.

[MedGen]

Meep, wrong. Reverse transcribing RNA to DNA is a purely viral phenomenon. Bacteria do not do this (refer to the dogma of molecular biology for details). It seems to me that you are also confusing transcription with replication.

 

My bold, this is a nit-pick, and I'm sure you didn't mean it, but LINE-1 mean anything to you? Not a reverse transcription isn't a virus only affair, unless you count transposable elements as virii because of their evolutionary past.

[CharonY]

Actually it is a good point. However I am disregarding retrotransposons for the same reasons I am disregarding viruses: both are mobile genetic elements. Their mechanisms of replication ensure their own persistence rather than having a real role for the host. Or in other words, the reverse transcriptase does not fulfill host functions.

 

In any case, while it is not my field of expertise I would not be surprised if these MGEs are likely precursors of viruses.

 

Edi: I see what you mean now. Yes I should probaly have said RTs are a phenomenon of mobile genetic elements. Good catch.

[MedGen]

I also forgot to mention processed pseudogenes also arise by reverse transcription.

[profescher]

Right I've gone away and cheked lots of stuff as i said i would. Not completly at the bottom of it as i am sure somewhere the things we are both saying marry up (though i'm starting to think it will be in a universe far far away) However i wanted to make sure i wasn't talking gobblygoosh (As my daughter says!)

 

Imidazoles have a wide variety of applications: Antibiotic use in the treatment of bacterial peritonitis, liver abcesses, pelvic abcesses, bacterial vaginosis, against anaerobic bacteria, in the treatment parasites, giardia lamblia, it is also used to treat infections caused by C. difficile and H. pylori. It is also used topically as spot cream. Incredibly there are still more uses, it is found in fungicides and anti-fungals, anti-protozaols and in anti-cancer drugs used to treat leukemia by interfering with DNA activities. According to the Journal of antibiotics:

 

Based on these observations and

considering the preferential inhibition of DNA

synthesis in vivo, we suspected that azomycin

possibly inhibits ribonucleotide reductase, the

enzyme catalyzing the step where the biosynthetic

route of deoxyribonucleotides branches

from that of ribonucleotides.

VOL. XXVII NO. 3

 

Azomycin being another imidazole. Imidazoles are a group of drugs that include antifungals and atibiotics, definitely worth a mention when giving an overview of how antibiotics work and why they are not specific to particular bacteria.

 

So if that's cleared up can we get back to the origonal question which still is not answered as fully as it could be?

 

I also checked on rifamycin (Too make sure i wasn't talking rubbish) and the following quotes with relavent links maybe useful.

 

From protective action of the template-primer and other data it might be suggested that the rifamycin derivatives act at an early step(s) in DNA synthesis catalyzed by reverse transcriptase. The obtained data are in agreement with the results for other derivatives of rifamycin SV described in literature

November 11, 1976.

http://nar.oxfordjournals.org/cgi/content/abstract/4/3/523

 

Rifampicin is a semi synthetic member of the rifamycins. It inhibits DNA dependent RNA polymerase, probably by interfering with the initiation of RNA synthesis, after the attachment of the polymerase but before nucleotide bond formation. The antibacterial action of rifampicin is due to the fact that it inhibits bacterial RNA synthesis without affecting RNA synthesis in the host.

http://www.microbiologyprocedure.com/bacterial-cheomotherapy/rifamycins.htm

 

New rifamycin derivatives have now been synthesized which are powerful inhibitors of

the RNA-dependent DNA polymerase of murine sarcoma virus (MSV) (Gurgo, Ray &

Green, I972). Especially active are the 3-oxime derivatives such as AF/o5 and AF/oI3

which also have been shown to inhibit DNA-dependent RNA polymerase by preventing

initiation of the RNA chains

http://vir.sgmjournals.org/cgi/reprint/17/2/221.pdf

 

3-(4-Methylpiperazinyliminomethyl)rifamycin SV

Rifampin

 

3-(4-Methylpiperazinyliminomethyl)rifamycin SV

Rifampin

 

Brick red solid. Antibiotic that specifically inhibits DNA-dependent RNA polymerase in bacteria by forming an inactive complex. Does not affect mammalian RNA polymerase. Inhibits transcription by preventing the initial transcription complex from entering the elongation mode

http://www.merckbiosciences.co.uk/Products/ProductDisplay.asp?catno=557303&

 

rifamycin

<drug> Antibiotic produced by Streptomyces mediterranei that acts by inhibiting prokaryotic, but not eukaryotic DNA dependent RNA synthesis. Blocks initiation, but not elongation of transcripts.

http://cancerweb.ncl.ac.uk/cgi-bin/omd?rifamycin

 

Or for the curious these links may be interesting.

http://www.antibioticresistance.org.uk/ARFAQs.nsf/2f87bc309e63df2d80256c8c004c707d/e424da333d67a98680256caa00393d78?OpenDocument

http://scienceaid.co.uk/biology/micro/antibiotics.html

[CharonY]

I never said that imidazoles did not include antibiotical compouds. Only that not all imidazoles are antibiotics. Imidzaole is the the collective term, antibiotics are but a subgroup. I wanted to clarifiy (and other points).

 

Your posts regarding rifamyicin only state what I said earlier. You do know what the function of the polymerase in question is, don't you (was there any point in posting them)?

 

The question to the original post has been answered a while ago, though.

 

I also forgot to mention processed pseudogenes also arise by reverse transcription.

Mobile genetic (retro-)elements did and do shape complex genomes. And there is more out there than that mentioned already. It is quite an interesting topic, though I would suggest opening up a new thread if you are interested in discussing it.

Edited December 16, 2008 by CharonY

[profescher]

Hmm this has gone on so long i wonder if we understand what each other is saying anymore.

 

To clarify, i am suggesting drugs in the rifamycin group such as rifampicin inhibit DNA synthesis by targeting DNA-dependant RNA-polymerase. Which not only has roles in making RNA but also effects DNA replication and thereofre DNA synthesis. I think you're saying Rifamycins don't inhibit DNA synthesis and DNA dependant RNA polymerases only make RNA.

 

So bearing that in mind. My last two articles and links and I'm done. If we can't agree on something, perhaps we should debate something else. But I would like to understand why you think i'm incorrect, cause maybe i'm missing it.

 

These findings indicate that a specific rifampicin-RNA polymerase interaction is responsible for blocking new DNA synthesis. It now seems plausible that RNA polymerase has some direct role in the initiation of DNA replication

Douglas Brutlag, Randy Schekman, and Arthur Kornberg

Department of Biochemistry, Stanford University School of Medicine, Palo Alto, California 94305

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=389535

 

The other you will have to read, the abstract covers it.

http://www.pubmedcentral.nih.gov/pagerender.fcgi?artid=288679&pageindex=1#page

 

And as i previously said the Oxford Handbook of Medical Sciences, published by OXFORD University Press, (one of the top universities in the world) states on page 789 table 12.1 the cellular target of inhibition is DNA Synthesis and specific targets are DNA dependant RNA polymerase, the class of drug is rifamycin, example is rifampicin, active against Mycobacteria, S. aureus, Legionella, brucella and rhodococcus equi, always given in combinations and mechanisms of resistance are mutations in RNA polymerase.

 

What do you think?

Edited December 16, 2008 by profescher

[CharonY]

OK let me try to clear it up a bit. The primary role of RNA-dependent DNA polymerase is the creation of RNAs, including mRNAs. Inhibition of the latter is the reason for the antibiotic effects of rifamycins. I have to admit that I am guilty of goading you a bit, as I was interested to see whether you really understood what you were saying, or whether you were just parroting.

 

Let me point out where you went wrong:

 

To synthesize DNA the cell must have an RNA copy and then synthesize the DNA using reverse transcriptase. If the production of RNA is inhibited so must the synthesis of DNA.

 

This is definitely wrong as the creation of DNA from RNA is the replication mode of mobile genetic element (wink) and not of the respective host organisms itself.

 

RNA-polymerase. Which not only has roles in making RNA but also effects DNA replication and thereofre DNA synthesis.

This is kind of half right. The RNA polymerase itself is not involved in DNA replication, but their products are. The most obvious one is of course that no mRNA is synthesized, including those required for DNA, but also (arguably more important) for all other cell functions.

 

 

Truth is, there is a link between RNA and DNA synthesis that you have not really mentioned, though. The papers hint at it, but they really dealt with replication of virus DNA. The papers actually identifying the link came much later (though there was already one in the 70s postulating a direct involvement, based on circumvential evidence).

One of the initiation modes of DNA replication near OriC is mediated by a DNA-RNA hybrid (that initiate the unwinding) and IIRC the RNA portion is synthesized by the RNA polymerase. I was waiting for you to point that out (and I may have been slightly impressed if you did).

 

But as I said, rifamycins inhibit all types of RNA synthesis mediated by the DNA-dependent RNA polymerase, not only those portions that pertain to DNA replication (otherwise you would have to categorize all antibiotics inhibiting protein synthesis also as DNA replciation inhibitors, as proteins are required for DNA synthesis...).

 

And as i previously said the Oxford Handbook of Medical Sciences, published by OXFORD University Press, (one of the top universities in the world)

And you think that is going to impress me or add anything to your argument? If you do not follow the content, showing off the cover will do nothing. And just btw OUP is a publisher as every other academic publisher the fact that it is a department of the university does not enhance its quality per se.

And while I do not have the book I am pretty sure that if did describe rifamycins as inhibitor of DNA replication, it was due to the fact that it was used extensively for experiments regarding the DNA replication mechanism. But once more: it was mostly used as a transcriptional inhibitor, often together with chloramphenicol (with the above mentioned exception).

Edited December 17, 2008 by CharonY

[MedGen]

profeshcer: DNA dependent RNA-polymerase catalyses mRNA production from a DNA template, RNA dependent DNA polymerase initiates DNA replication by priming with RNA which is later degraded and replaced by DNA. DNA synthesis itself (replication) is mostly an RNA-free affair, with the exception I've noted. So if an antimicrobial compound inhibits DNA synthesis then it prevents the cells replicating. If it inhibits RNA synthesis then it prevents transcription and thus gene expression. Importantly these are two distinct mechanisms and it is worth noting that.

 

This isn't an issue for debate, it is whether or not rifamycin inhibits replication or transcription, and your current inability to differentiate between the two.

 

NB Note that a medical handbook will generally gloss over the specific mechanisms of drug action, but you are still mistaken.

 

edit: crap, missed CharonY's post above

[CharonY]

Just wanted to add that normally only the initiation at the origin requires the RNA polymerase. The rest of the priming is conducted by the rifamycin resistant primase.