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Uselessness of useful antibiotics
Not long ago it was widely believed that human health would no longer be threatened by serious bacterial infections. Bacterial diseases such as tuberculosis, pneumonia, gonorrhoea and dozens of others would be stopped by administration of antibiotics — compounds that would selectively kill bacteria without harming the human body. However, bacteria that were once susceptible to a variety of antibiotics are becoming increasingly resistant to them.
The development of bacterial resistance provides an excellent example of natural selection. The widespread use of various antibiotics has killed off the susceptibility of bacteria.
The result has been a marked upswing in the incidence and virulence of a number of diseases caused by streptococcal and staphylococcal class of bacteria. Many infectious disease specialists are predicting that the problem will become more acute in the coming years and that fatality of once curable diseases will increase sharply.
The chemical structure of the antibiotics of penicillin and cephalosporin groups are provided with a four membered beta-lactam nucleus which incites bacteria to counteract by producing enzymes called beta-lactamases, which hydrolyse the antibiotics rendering them useless. Bacteria of the class of Staphylococci are regarded as the principal ones for producing beta-lactamases. The genes which code for beta-lactamase enzymes are located on plasmid of bacteria whence the enzyme is transferred by the process of transduction. This renders the antibiotics ineffective and useless.
Beta-lactam antibiotics include a broad class of antibiotics. They include penicillin derivatives such as ampicillin and amoxicillin and cephalosporins which are widely used for the treatment of various types of infections. Clavams, Cephamycins and Carbapenams are other members of Cephalosposrins with beta lactam nucleus.
-C=O -C-OH
l ll
NH N
Lactam — Lactim
Lactam is a cyclic amide formed from aminocarboxylic acids by the elimination of water. Lactam are isomeric with lactim which are enol forms of lactams. This is carried out by chopping the linking nitrogen of the thiazolidine part of the molecule to the adjacent carbonyl carbon. This breaks open the beta-lactam ring of antibiotic rendering them useless. At the time when penicillin was first introduced as an antibiotic during World War II none of the major disease causing bacteria possessed the ability to evolve beta-lactamase enzyme.
This has been verified by examining the genetic material of bacteria obtained from laboratory cultures of pre-antibiotic era. Today with the passage of time and changing circumstances coupled with modified lifestyles, bacteria have also changed their lifestyle. They have developed the ability to defend themselves by producing enzymes called beta-lactamases which help fight out their killer antibiotics. Production of beta-lactamase is the primary cause of penicillin and cephalosporins becoming useless.
a) The production of beta-lactamase, however, does not rule out the treatment of beta-lactam antibiotics. Some patients may get well with beta lactam antibiotics. It depends on their own genetic make-up. It is said that all drugs do not suit all the patients.
Clavulanic acid is also a beta-lactam antibiotic but its chemical structure is such that it cannot induce the production of beta-lactamase enzyme in bacteria. Ampicillin and Amoxycillin penetrate bacteria and inhibit third and final stage of cell wall synthesis which leads to cell lysis. Ampicillin is also used in molecular biology as a test for uptake of genes by plasmid. A gene that is to be inserted into bacteria is coupled to a gene coding for an Ampicillin resistance usually bla gene coding for beta-lactamase. Bacteria that take up the desired gene become Ampicillin-resistant.
Components of the system by which bacteria duplicate themselves, transcribe and translate genetic information enabled the scientists, during the last forty years, to introduce a number of synthetic antibiotics to pharmacologists and medical professionals for the treatment of infectious diseases. These include Rifamycin, an antibiotic that selectively inhibits the bacterial RNA polymerase, the enzyme that transcribe DNA into RNA. It becomes useless due to alteration as determined by chromosomal mutation.
Similarly, streptomycin and tetracycline bind to bacterial ribosome but not the human ribosome. Ribosome is one of the components of all the living cells upon which protein is synthesized. Tetracycline inhibits the infective bacteria by competing with transfer RNA — a vehicle which helps select amino acids used in synthesising the protein of all living cells. This renders the bacteria inactive and the disease is avoided. But when the antibiotic is assailed by plasmid-mediated resistance due to decreased accumulation of the drug they face inducible resistance proteins which promote energy dependent efflux of the antibiotics which finally becomes useless.
Streptomycin and aminoglycosides act by causing a misreading of the message coming from infective bacterial DNA to synthesise protein to enable it to cause disease. This misreading inhibits bacterial activity and the bacteria are routed out. But these antibiotics become useless by phosphorylation adenylaltion or acetylation in their molecules.
Chloramphenicol acts by inhibiting the transpeptidation of bacterial protein which otherwise would activate the bacteria to elaborate the disease. Uselessness of Chloramphinicol is brought about by acetyltransferase produced by resistant bacteria. Erythromycin acts by translocation of bacterial transfer RNA. This process inactivates the bacteria.
Erythromycin is rendered useless because its binding site with PBP is altered due to plasmid mediation. The antibiotics of 4-quinolone group, such as nalidixic acid and ciprofloxacin act by inhibiting DNA gyrase, thus providing the winding of DNA helix of bacteria into super coiled form.
The widespread occurrence of the beta-lactamase gene illustrates how readily gene can spread from one bacterium to another, not only among the bacteria of a given species, but among various other species too. This can happen in several ways including conjugation in which gene processing DNA is passed from one bacteria to another; transduction in which a bacterial gene is carried from one bacteria to the other by a virus and transformation in which a bacteria is able to pick up naked DNA from its surrounding medium. Scientists have attempted to counter the spread of beta-lactamase by synthesising penicillin derivatives that are more resistant to the hydrolytic enzyme.
As might be expected natural selection quickly produces bacteria whose beta-lactamase can split the new forms of the antibiotic. A single base change — a change in one of the four components of DNA in a gene encoding a bacterial beta-lactamase — may render million dollars’ worth of pharmaceutical research effort useless.
One approach that has met with limited success is to treat patients with two separate drugs: a penicillin-like antibiotic to inhibit the transpeptidases and a separate enzyme inhibitor such as clavulinic acid to inhibit the beta-lactamase. Sulbactam a beta-lactamase inhibitor used as the sodium salt to increase antibacterial activity of penicillins and cephalosporins against beta-lactamase producing bacteria. Some are still resistant because they possess modifications in their cell walls that block entry of the antibiotic; others are resistant because they are able to selectively export the antibiotic alone that has entered them; still others are resistant because they possess modified transpeptidases that fail to bind the antibiotic.
Bacterial meningitis, for instance, is caused by the Neisseriae meningitides which has yet to display evidence of having acquired beta-lactamase producing ability. Yet these bacteria are becoming resistant to penicillin because their transpeptidases are losing affinity for the antibiotics.
Comparisons of the genes encoding the resistant transpeptidases with the genes encoding the corresponding enzymes in susceptible bacteria (isolated from the cultures of the antibiotic era) reveals major differences in sequences of DNA components. These findings indicate that the bacteria are not becoming drug resistant as the result of genetic mutation, which would produce small genetic changes, but rather by acquiring new genes from another species.
The antibiotics usually act on certain predetermined targets in the bacteria. Such antibiotics also require a certain amount of concentration to be effective. Certain bacteria alter their permeability thus not letting sufficient amount of drugs to enter them and cause their actions. These mechanisms are indeed due to genetic mutation. This could be either a chromosomal mutation or the acquisition of a plasmid or transposon.
Plasmids: These are regarded as extra-chromosomal circular DNA molecules that carry the genes which code for a variety of enzymes responsible for the mechanisms that mediate the antibiotic resistance as described above. Usually plasmid-mediated resistance is considered to be most important because it occurs in many bacteria and they frequently mediate resistance against multiple drugs. Plasmids have very important properties and they can be transferred to different bacteria. Transposnes, also called jumping genes, are transferred either between or within large pieces of DNA.
Excessive use of multiple antibiotics and prescribing them unnecessarily for long courses of therapy leads to suppression only of susceptible bacteria. The resistant bacteria survive because of the rapidly dividing nature of bacteria. In general, such resistant bacteria are produced in large numbers and spread throughout the community. Moreover, these bacteria can transfer their resistant properties to other previously susceptible organisms through plasmids.
It should be remembered that while using antibiotic drugs the single best drug whenever possible should be chosen. Drug combinations involving two or more antibiotics should only be given when indicated, such as tuberculosis and/or treating infections before the identity of the bacteria is known.
Sometimes it is the patient who is responsible for generating resistance in the bacteria that has infected him. Such patients may begin an antibiotic regimen; when they begin to feel better they stop taking the medicine before completing the full course and save the remaining tablets for another time because of emergency or economic reason. This renders some bacteria to stay in the body un-annihilated and hence develop immunity to these drugs.
According to WHO, around 14,000 people are infected and die each year because of drug resistant microbes found in the US hospitals. Globally drug resistant bacteria account for up to 60 per cent of hospital acquired infections. The WHO also claims that almost all major infectious diseases are slowly becoming resistant to existing medicine in various parts of the world.
Antibiotics’ uselessness can also occur in sub-standard storage conditions and manufacturing at the hands of unscrupulous people having no sound knowledge of chemistry and pharmaceutics.
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