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Bacteria have evolved numerous strategies for resisting the action of antibiotics and antibacterial agents. This is particularly true of those bacteria that are antibiotic producers. Bacteria that produce antibiotics do so to gain a selective advantage over other, competing microbes in their natural environment.
Antibiotic resistance can be described as microbiological or clinical. Microbiological resistance exists when the organism possesses any resistance mechanisms. Clinical resistance can be explained as failure to achiever a concentration of antimicrobial that inhibits the growth of the organism in a particular tissue or fluid
Bacteria become resistant to antibiotics by a very simple method of natural selection. When a large number of bacteria are presented for the 1st time with an antibiotic, most if not all of them die off. If all of them die; then obviously no resistance is gained for that particular bacterial colony.
Resistance comes about when one or even more bacteria survive the initial exposure. This because they were previously resistant before exposure to the antibiotic. After they survive the exposure, they reproduce themselves and make a new colony of bacteria; every bacterium in the colony is a clone of the original resistant bacterium and so all of the are resistant to that antibiotic to the same degree.
The question now is how did the first or two resistant bacteria survive to pass on their evolved resistance to their offspring? Resistance to a particular agent may be accomplished by more than one resistance mechanism. But it is important to understand the target processes that antibiotics target so as to understand how resistance comes about.
There are two main targets that antibiotics attack. These are;
Bacterial Protein synthesis
Aminoglycosides and macrolides are antibiotics that target the bacterial protein synthesis. They work by blocking one step or another in the process of protein production. They bind to the small sub-units of the ribosome which is used in the recognition of the anticodon of tRNA and the codon of m|RNA and significantly interefers with the fidelity of the whole process. It is therefore evident that any change that affects the binding of aminoglycoside antibiotic would block their adverse effect on protein synthesis thus giving the bacteria resistance to this type of antibiotics
Bacterial nucleic acid replication and repair.
Like protein synthesis,antibiotics target this process. Fluoroquinolones .i.e. ciprofloxacin, are syntetic antibiotics that target both DNA gyrase as well as topoisomerases. They inhibit or interfere with their functions and by so doing slowdown or totally inhibit nuclei acid replication and repair. In gram positive bacterial species fluoroquinolone resistance is the result of a single point mutation on the 'quinolone resistance determining region'.
Bacteria may display antibiotic resistance by one or more of the following mechanisms:-
Alternation of the antibiotic target
This is probably the most common mechanism of antibiotic resistance. When an antibiotic binds to its target, it limits the targets ability to perform its normal functions. So if a mutation occurred that blocked that antibiotic's ability to bind to the target, the antibiotic would loose its ability to hinder the function of that target. The action of many types of antibiotics is successfully prevented by such mutations.
Modification of the antibiotic target is often seen in laboratory generated mutants. For example, bacteria resistant to trimethoprim produce an alternative dihydrofolate reductase. Resistance to the quinolone antimicrobials results from point mutations in the gene encoding DNA gyrase. Aminoglycoside resistance may result from modifications of the ribosome structure. Indeed, in the laboratory ribosomes may be further altered so that they only function in the presence of aminoglycosides. The drug acts to stabilise the functional ribosome in aminoglycoside-dependent bacteria.
Meticillin resistance in meticillin-resistant Staphylococcus aureus results from the production of an additional penicillin binding protein: PBP2', which is not susceptible to inhibition by penicilli.
Restriction of the antibiotic access to the target
Peptidoglycan in Gram-negative bacteria is inaccessible to penicillins that cannot penetrate the Gram-negative outer membrane. The thick mycolic acid layer of protection produced by mycobacterium and an outer lipid membrane produced by gram- bacteria limit a large variety of antibiotics from reaching their targets. Having a target that is inaccessible to antibiotics may be achieved in a variety of ways.
The outer membrane of Gram-negative bacteria may act as a permeability barrier for antibiotics. Many Gram-negative bacteria are intrinsically resistant to antibiotics like benzyl penicillin because such drugs cannot penetrate the outer membrane and so cannot reach their target.
For gram- bacteria in particular, glycopeptides are specifically limited in access to their Peptidoglycan precursor's targets in gram- bacteria because glycopeptides have large hydrophobic structures in their molecular make up that cannot readily cross the gram- cell's outer membrane.
Another method of limiting antibiotic access to target sequences is found in the case of macrolide resistance where the macrolide antibiotics like erythromycin and azithromycin are actually 'pumped' out of the cell. The pump can get rid of the antibiotic faster than it can accumulate in the cell.
One type of the pump is produced by the 'MeFE' gene. This gene produces a 12-transmembrane-helix macromolecule which exports 14 and 15 memberedmacrolides from the cell,giving the cell resistance to antibiotics such as erythromycin. As many as 85% of erythromycin resistance strains habour the MeFE gene.
Gram-negative bacteria resist the activity of tetracyclines by this important mechanism. Resistance is as a result of failure of the antibiotic to reach an inhibitory concentration inside the bacterium. This is due to plasmid-encoded processes that either reduce uptake of the antibiotic or enhance the antibiotic's transport out of the cell.
Inactivation of the antibiotic
Many clinically important bacteria produce enzymes that are capable of chemically modifying or destroying antibiotics. Chloramphenicol may be acetylated by the action of chloramphenicol acetyltransferases. Aminoglycosides may be acetylated by aminoglycoside acetyltransferases, phosphorylated by aminoglycoside phosphotransferases or conjugated with nucleotides. Such modifications render the antibiotic inactive.
Antibiotics may also be enzymatically degraded to an inactive form. The ï¢-lactam bond can be hydrolysed by a large family of enzymes known as the ï¢-lactamases. Some ï¢-lactamases have a preferential activity against penicillins and these are referred to as penicillinases. Cephalosporinases are more active against cephalosporins.
Staphylococci have been associated with the production of ï¢-lactamase for many years. Early in the history of the development of semi-synthetic penicillins, compounds were manufactured that were able to resist the activity of staphylococcal penicillinase. These drugs had side-chains that prevented the staphylococcal ï¢-lactamase from binding to the antibiotic and hydrolyzing it.
Lack of a target for the antibiotic
Not all bacteria have Peptidoglycan in their cell wall. Rickettsias and chlamydia, for example, lack peptidoglycan. Such bacteria are intrinsically resistant to the action of cell wall inhibitors such as the penicillins and cephalosporins. This is because they do not have the site the antibiotic specifically targets.