Wikipedia holds a nice survey and appropriate links

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

If you google "mechanisms of antibiotic resistance", you get nice reviews.

Both.

Some genes are constitutive (resistance gene were found in bacteria from unvisited cavern hence with no previous contact with antibiotics nor men) and some are inducible, under the pressure of antibiotics. It's also a way to classify antibiotics resistance, in itself.

There are different antibiotic resistance mechanisms, and genes coding are located in the chromosome and in plasmids so they are also different. The regulation of genes is complex. There are many books, some of them are already listed.

Wikipedia holds a nice survey and appropriate links

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

If you google "mechanisms of antibiotic resistance", you get nice reviews.

There are cases of either constitutive or inducible resistance genes. The VanSR and VanHAX system is a paradigmatic example of inducible resistance genes. Some attemps have been performed to target the regulatory system VanSR by His kinase inhibitors.

Antibiotic resistance genes can become extrachromosomal (e.g.. plasmid) and will be amplified under selective pressure. This is a major pathway for antibiotic resistance regardless of whether the parent gene is constitutive or inducible. Extrachromosomal amplification plays a major role in eukaryotic drug resistance, particularly in tumour cells.

Hi!

You can find several papers regarding the subject and even books.

Of course you can target regulons to control resistance genes expression, but you have to know which species you are going to work with, as they vary according to the pathogen.

Gerard, i agree completely with your position, constitutive antibiotic resistance genes are well distributed in a number of pathogenic bacteria, however they are silent or in a quiescent state. Upon epigenetic pressures such as indiscriminate use of antibiotics, the hitherto quiescent genes are activated to affect the metabolism of a particular antibiotic, particularly its biological half life in the host. This effect on the pharmacodynamic profile of antibiotics leads to the phenomenon of antibiotic resistance.

Yes, you are right the antibiotic resistance genes can be both constitutive and and inducible in general.

Targeting regulatory genes/protein products is a viable approach to combat resistance provided you understand at a molecular level the signals that induce or suppress expression of the resistant genes. For example, if a specific small molecule binds and induces expression then inhibitors can be designed. If induction is in response to a more global cell state such as stress, it would be difficult.

What is the purpose for bacteria to produce resistance genes constitutively, if there are not harmful antibiotics present? I know some antibiotics have some other functions such as signaling, as some people pointed out in recent literature. Possibly, the constitutively-expressed resistance genes can interfering bacterial signialing.

Bacteria live in environment where many other organisms live, including fungi. Thus due to high competition they need to survive and to be resistant to antibiotics - natural substances produced by other organisms. At least by this reason some genes are constitutive.

Antibiotics are probably accidental substrates of efflux pumps encoded by constitutive resistance genes because they have similar effect on a cell like the natural substrates of the pumps. Check the articles below;

BMC Microbiology 2011, 11:252 doi:10.1186/1471-2180-11-252

Nature Reviews Microbiology 4, 629-636 (August 2006) | doi:10.1038/nrmicro1464

http://www.biomedcentral.com/1471-2180/11/252#

@Modestas Ruzauskas

@Alex Boye

@Gerald Waneck

The literature says there are two school of thoughts. As they live in environment full of fungi producing antibiotics these organism develop battery of genes to combat antibiotics. another school of thought suggest they evolved along with their evolution to produce antibiotics. Simple example would be for organisms producing restriction enzymes have their DNA methylated to protect themselves. Like that organism producing antagonistic products also have genes to protect themselves. That may serve the purpose for bacteria to produce resistance genes constitutively. But when slowly when antibiotic pressure increases in their environment they can induce their master operon to combat antibiotics.

As with many questions, the answer depends. Tetracycline resistance genes are examples that are clearly inducible. Streptomycin resistance is often not inducible, as it may involve a simple target site modification, so no need for induction.

Hi Daniel,

What a great question! One way of targeting "inducible" virulence genes is through targeting quorum sensing (qs) mediated gene resistance. Ex.- in Pseudomonas aeruginosa things such as biofilm development, efflux pump expression, pyocynin production, ect. are all under qs control. So, there are some compounds such as penicillic acid, putulin, various furanones. These compounds inhibit the expression of these pathogenic genes, without killing them. So, it's like having an army but taking there guns away....population count is high enough is high enough for the immune system too be notified but the bacteria defenseless. The reason we have yet to see drugs these on the market is because 1) the science is relatively new, 2) most of the compounds they've found so far are toxic, 3) testing development is a nightmare.

There are opportunities to modify the bacterial- bacterial interactions on several ways both in vitro and in vivo:

e.g. by elimination of varius plasmids, inhibition of horizontal plasmid transfer.

Other targets can be modified e.g. by inhibition the quorum sensing signal transmission at the population level by some natural compounds, essential oils, proton pump inhibitors. some Ca channel inhibitors and 5FU.etc

Every single living thing has their own defensive tool(s)/ mechanism. This also applies to microorganisms such as bacteria. Although the event might be inducible, but the machinery its self is available. Different environmental cues will induce different element in defense system to be active. For example, in P. aeruginosa, different organelle will be assembly at different environmental condiition. Organelles themselves are the result of the expression of different proteins/ enzymes as a part of a bigger entity (the machinery/ the switch). So, if we can understand this switch, then more likely we can find/ at least design a certain molecule to inhibit if not eliminate the action of the machinery......

Maybe from the first time the antibiotic producing microorganisms create their own defensemechanisms agints specific molecules save in the genome...

Antibiotic resistance genes of microoganisims can be inducible depending on faced their environment live. Some commensal microoganisims can be acts as a reservoir of antibiotic resistance genes.

remember this is again a question of thermodynamic, drug transport and hydrolysis, and again a problem of cost for living cell.. Genetic cascade, such as Mar operon controlling way, can modulate the resistance level. Consequently, bacterial adaptability balances the expression of genes involved in drug resistance/tolerance e.g. porins, efflux pumps, LPS alterations, enzymatic production, ....

Agree with J. Hernandez: Actinomycetes start production of an antibacterial when secondary metabolism is triggered. In the gene cluster for antntibacterial production also genes for resistence are encoded, that are so expressed only together with AB production.

Antibiotic resistance genes can be both constitutive and inducible. It is vary among the organisms e.g ampC gene in Escherichia coli is not inducible, because the regulatory gene is absent, so it is constitutive while in case of Yersinia enterocolitica it is inducible.

How about resistance genes on plasmids? Many bacteria get resistance genes through horizontal gene transfer. Do those genes have repressor (genes) going with them? If not, does it mean that they are consititutive?

I don't think there is a clear answer for this question. In other word, it is complicated. Some antibiotic resistant genes are located on plasmids, so once the bacteria acquired threes plasmids naturally, they also gain resistance to the antibiotics.

Antibiotic resistance could be induced by exposing to antibiotics as well. The bugs can develop resistance by modification of antibiotics, by alternate the antibiotic targets, or by pump antibiotics out of cells. All these mechanisms could be induced by exposure to antibiotics.

I antibiotic producers, on the other hand, antibiotics are synthesized by sequential enzymatic reactions with enzymes encoded by gene clusters. Generally, an antibiotic biosynthetic gene cluster consists of biosynthetic genes meaning genes encoding enzymes catalyze biosynthesis, regulatory genes meaning they are responsible for turning on and off the biosynthetic pathways, and resistant genes meaning the producer won't be killed by it's own products.

There are more mechanisms for antibiotic resistance, and some are still unknown.

Some resistance genes are inducible by the antibiotics to which they confer resistance, e.g., macrolides can induce RNA methylase genes (erm(B)) and macrolide efflux genes (Mef and MsrD). Ribosomes bound by an inducing macrolide pause during translation of these genes which ultimately leads to resolution of transcriptional or translational attenuators. Expression of these genes likely exerts a fitness cost on the bacterium making it advantageous to express only when absolutely necessary. Other ribosome-targeting drugs, i.e., tetracyclines and chloramphenicol can be inducible as well. B-lactam resistance can be inducible through B-lactamase gene expression or cell wall modification, though the latter requires a more global response than induction of a single, or a few, genes

Targeting the expression of inducible resistance genes is theoretically possible and is an approach that is being pursued.

Regulation of plasmid-encoded resistance genes is a factor of plasmid-encoded regulation, host-encoded regulation and, of course environment,. So they may be constitutive, inducible or variable.

The attached review may be helpful.

It's a very wide and complex topic for explaining it in this short space. Anyway, in whole, chromosomally-mediated antibiotic resistance is usually, in first instance, inducible. Constitutive production of resistance factors would be an unnecessary expending of resources in an antibiotic-free environment, and thus usually emerges only through mutation of normal control mechanisms and selection by antibiotic selective pressure.

It depends on the mechanism. With the exception of Klebsiella pneumoniae (which typically lacks this gene) and E. coli all chromosomal AmpC beta-lactamases in Enterobacteriaceae are regulated by AmpD, for instance. Over-expression mutations can arise from mutations that result in the gene being "always on".

Each resistance determinant may have its own regulator. Plasmid and integron borne resistance determinants are mediated by the upstream regulators present in those genetic elements. The AmpD regulator is sometimes found upstream of plasmid-borne beta-lactamases.

In short, both occur, depends on bacteria, antibiotic, determinant and genetic context.

Both occur. Depends upon the lineage and the source of collection (known/unknown).

Modulation of gene expression can occur at the transcriptional or translational level following mutations or the movement of mobile genetic elements and may involve induction by the antibiotic. In the latter case, the antibiotic can have a triple activity: as an antibacterial agent, as an inducer of resistance to itself, and as an inducer of the dissemination of resistance determinants.

Yes, they can be both inducible or constitutive.

Very small amount of antibiotics in the environment are able to contribute to maintain antibiotic resistant or multidrug resistant bacterial strains as the consequence of environmental polution, that we can call "natural selection" resulting in the permanent source of antibiotic resistance in microbes.

The effect can be similar to the effects of"electro-smog" in the induction of some malignacies for the world population.

Nature has given bacterial and other organisms to overcome hazardous environment contaminated with toxic/ undesirable elements/antibiotics, through activation of certain genes either located in the chromosome or extra-chromosomal DNA (PLASMID) or both and thus in general these genes are always inducible and regulated. There may be bacterial genes that could be rarely constitute in nature but needs validation of expression and regulation of such genes that are constitute and such microorganisms could always remain resistant to many antibiotics and may be dangerous to mankind. There are many bacterial pathogens in nature that are still sensitive to very many different antibiotics and drugs though they could develop resistance rapidly as antibiotics/drugs are made easily available in the environment. The activated antibiotic resistance genes in turn produce enzymes/ proteins/ molecules that are helpful to modify/metabolize the toxic components to nontoxic forms/ or pump out of the cellular machinery. Drug resistance genes from other organisms can also be imported from the environment into the bacterial cells and could be incorporated into it:s genome. This area of drug resistance is evolutionarily, functionally and practically very important for each kind of microorganisms as well as for the survival of mankind.