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Transcript
With appropriate examples, describe the different types of mechanism that make bacteria resistant to antibiotics. When bacteria become resistant to antibiotics it is easy to forget that even the most resilient of these can be inhibited or killed by a sufficiently high dose of antibiotic. Unfortunately, patients can’t always tolerate this critical concentration. There is huge variability in antibiotic susceptibility across different bacteria. For example, most streptococchi pneumoniae are inhibited by 0.01mg/l of benzylpenicillin, whereas with E.Coli around 5000 times more is needed which would be dangerous to the body. There are four main mechanisms of antibiotic resistance: antibiotic inactivation or modification; alteration of target site; alteration of metabolic pathway; and reduced antibiotic accumulation. Antibiotic Modification Of the four mechanisms the most well known is the antibiotic modification where there is no change to the target site but instead the antibiotic is prevented from reaching the target site. The prime example of this is beta lactamases which enzymatically cleave the beta lactam ring on the antibiotic rendering it inactive. Some beta lactamases are quite general whereas others are more specific (ie. staphylococchus aureus penicillinase) though most will have some effect on penicillins and cephalosporins. Beta lacamases are characteristic of both gram positive and gram negative bacteria though only some show significant inhibition to beta lactamase inhibitors such as clavulanic acid. Reduced antibiotic accumulation When bacteria display this type of resistance they protect their target site (which is, again, unaltered) by either preventing the antibiotic from entering the cell or pumping it back out faster than it can flow in resulting in only very small concentrations of antibiotic in the cell and hence very little effect on the target site. In gram negative bacteria, beta lactam antibiotics gain access to the cell via a water-filled porin protein channel. Pseudomonas aeruginiosa are resistant to imipenem antibiotics because they lack the specific D2 porin channel through which the imipenem gains access to the cell. Some antibiotics (ie tetracyclines) can enter certain resistant bacteria but are pumped out again by an energy dependent transport pump hence preventing the accumulation. Alteration of the target site Some bacteria achieve resistance through changing the shape of the target site therefore reducing the affinity of the site for the substrate. Enterococci are a good example of this as they are inherently resistant to cephalosporins because the enzyme (known as penicillin binding protein) responsible for the production of peptidoglycans (and therefore the cell wall) has low affinity for them and hence don’t bind strongly enough to inhibit the cell wall production. A good example of acquired resistance is streptococcus pneumonia which is usually highly susceptible to penicillin and cephalosporins. These Strep. Pneumoniae can encorporate DNA from other bacteria which cause the expression of a different penicillin binding protein and hence the cephalosporins no longer bind with enough affinity to inhibit the proteins. Alteration of the metabolic pathway The final mechanism of bacterial resistance involves the production of a different enzyme which is not susceptible to the antibiotic which performs the same function as the protein that is susceptible. The most famous example of this is MRSA (methicillin resistant staphylococchus aureus) which expresses an alternative penicillin binding protein (PBP2a) as well as the normal PBP. The PBP2a is not inhibited by the antibiotics usually used against staph. aureus such as flucloxacillin and hence the cell continues peptidoglycan production and therefore its cell wall is structurally sound. One of the major antibiotics used against MRSA now is vancomycin. However, when vancomycin resistant enterococci were discovered, it meant that potentially MRSA could adopt the vancomycin resistant gene cluster and become vancomycin resistant itself. This is also an example of the alternative target site mechanism as the resistant protein produced has a slightly different site which the vancomycin cannot bind to and hence cell wall synthesis continues. Where do ‘new’ resistance mechanisms come from when previously susceptible bacteria become resistant to antibiotics? Antibiotic resistance in bacteria can be intrinsic or acquired. Intrinsic resistance is when a bacteria has the gene in its genome which makes it resistant – ie. vancomycin resistant Escherichia coli. Acquired resistance can come about due to mutation or by acquisition of foreign DNA and is when a bacterium that was previously sensitive to an antibiotic is no longer sensitive. Whether in the presence of antibiotics or not, mutations are always spontaneous. Often these mutations are fatal to the bacterium. However, occasionally mutations can produce genes coding for advantageous phenotypes such as alternative penicillin binding proteins. The susceptible cells are rapidly culled in the presence of an antibiotic leaving on the newly resistant one (or few) which can then thrive thus a resistance subpopulation is produced. It is essentially massively accelerated “natural” selection. These mutations can actually then be passed onto non-resistance bacteria via horizontal gene transmission whereby plasmids (small self-replicating circular pieces of DNA) can be passed from one bacterium to another when they get close enough to each other. These plasmids can carry many resistant genes each which can then be incorporated into the previously susceptible bacterium’s genome by a transposon (jumping gene). It is likely that the spread of the mecA gene in MRSA was caused by this transposition. Another important process is transformation. When bacteria are infected by bacteriophages and die they release their DNA which can be taken up by other bacteria thus transferring any useful genes to the new bacteria. This is most commonly seen in staphylococci and is probably the main method for the spread of penicillin resistance in staph pneumonia (mosaic PBP genes are resistant to many types of penicillin).