(Chunyong Ding,Xiaorong Yu,Xiaojian Wang,Xiaoling Hu,
Chaonan Zheng, Xianfeng Miao, Yanyan Shi)
KEY WORDS: Bacteria’sdrug-resistance; PBPs; The efflux pump; Beta-lactamase
Since the discovery of penicillin, theantibiotics have served as effective arms against bacteria. But now thesituation is changing: because of the abuse of the antibiotics, more and morebacteria become drug-resistance and also they can develop their resistance tothe drug in a very short time, as we can see from the picture below:
And another big conscious: vancomycin ,a lastdefense against bacteria, which is called “last resort” is breaking apart!Vancomycin-resistant enterococci was first reported in England and France in 1987,and appeared in one New York Cityhospital in 1989. By 1991, 38 hospitals in the United States had reported the bug.A frightening report came in 1992, when a British researcher observed atransfer of a vancomycin-resistant gene from enterococcus to Staph aureus inthe laboratory. Just imagine that if the vancomycin resistance has spreadwidely, what should we do?
There is no doubt that weare in a very
serious situation, lots ofwork is needed
to deal with suchproblems.
First we’d better learn how the drug-resistance rises?
Under the selective pressure, it’s a natural problem, not an accident,but a fact of evolution. We candraw the following equation:
ANTIBIOTICS+BACTERIA=DRUG-RESISTANCE
The antibiotics work as follows: Reach its target, bind it and interfereit. So the bacteria can become drug-resistance in the corresponding followingthree ways: First, the drug can’t reach its target. Second, the drug wasdestroyed or degraded. Third, the target was changed.
Now, we are going to discuss the threemechanisms respectively:
First: the drug can’t reach its target.
The bacteria are divided into two classes---gram-positiveand gram- negative by the Gram stain. The surface of gram-negative bacteria aremore complex, and the inner membrane (which is analogous to the cytoplasmicmembrane of gram-positive bacteria) is covered by the outer membrane. It functionsas an impentrable barrier for some antibiotics.
① The outer membraneproteins (omps) penerate the outer membrane, with a narrow channel in themiddle, which allows the small hydrosoluable moles to go through. Beta-lactamantibiotics can also diffuse into the cell through the channel because of theirparticular structures. So the omps play an important part in bacteria’sdrug-resistance.
The change in their structures, the decreasein their number the missing and mutation can prevent the drug from entering thecell.
Recently lots of researches suggest ,there are lots of protein-F on theouter membrane of the S.aureous. The diameter of the channel is only 2.2 nm andthe narrowed part of the channel is charged, because of the electricstaiceffect and the narrow channel, many antibiotics can’t get into the cell.
Another extreme example is aerginosa, whichis intrinsically resistant to a wide variety of antibiotics by lacking of the classical high-permeability porins.
② Bacteria also have effluxpumps that may transport drugs out of the cell. Resistance to tetracycline andto beta-lactam antibiotics is an example of an efflux pump mechanism. Thefollowing figure depicts multiple components that can mediate bacteriaresistant to beta-lactam antibiotics.
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Second, the drug was destroyed or degraded.
Inactivation of the drug is the secondgeneral mechanism of drug-resistance.
The typical example is, beta-lactamantibiotics, which have a common four numbered beta-lactam ring, can bedegraded by the beta-latamase. Now, let’s look into its particular structure:
As could be seen in the picture, the activecenter, which is called “binding cavity”, is organized by four parts, SXXK,KTG, SDN and Ω-circle, and the active center is SER located in “SXXK”, in thecenter of binding cavity. The “-OH” and “-NH” of SER and the “-NH” of Ala contribute togetherto the formation of “Michaelis”. KTG and SDN play animportant part in the stability of the whole structure, while the Ω-circleis necessary in fixing the position of the water. What’s more, the bindingcavity can strengthen its power by changing its own structure, it could becomelooser for big substrate.
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Third: the target was changed.
The bacteria’s cell walls give them the shapeand protect them from osmotic lysis and toxic substance, so the tacit cell wallis crucial for the cell. Because bacteria’s cell wall distinguishes it from thehost cell wall, unfortunately it also becomes the target of many antibiotics.
Let’s review the biosynthesis of thecell wall: first the peptidoglycan subunit (containing one side-chain andattached peptide to be used in the cross-bridge formation) was synthesised inthe cytoplasm, then was carried out by the carrier, then the sugar portion ofthe peptidoglycan subunit was linked to the glycan backbone. the final stepinvolves the completion of the cross-link. This is accomplished by atr医学考研网anspeptidation reaction that occurs outside the membrane. The terminal glycanresidue of the pentapeptide is linked to the fourth residue of the pentapeptide(D-lactam), releasing the fifth residue (also D-alanine). It is the last stepin peptidoglycan synthesis that is inhabited by the beta-lactam antibiotics andvancomycin.
For vancomycin, it binds to theD-alanine-D-alanine terminus of the cell wall thus sterically inhibit thecross-linking. Then lacking the dense and inter-connected network, the cell wall maybecome fragile and senstive to the enviroment, and finally burst out. But the bacteria (enterococcal) becomevancomycin-resistance by the alteration of the D-alanyl-Dalanine to theD-alanyl-D-lactate or D-alanyl-serine, which bind vancomycin poorly, because acritical site for hydrogen bonding is missing. Than the bacteria can also add aamino acid (which is much larger than the alanine) to the end of the peptidechain, thus vancomycin can’t bind any more. Also the bacteria can change thecomposition of the cell wall by strengthing the thickness of the cell wall andreducing the cross-linking structure. So vancomycin has little influence on it.
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For beta-lactam antibiotics, lots ofresearches suggest that, They can binds with the penicillin-binding proteins,which is membrane-bounded, and inhibit its activities. All bacteria haveserveal such entities. For example, the high-molecular-weight PBPs ofE.coli(PBP 1a and PBP 1b) include the transpeptidases responsible for thesynthesis of the peptidoglycan, other PBPs in E.coli include those that arenecessary for septum formation at division.
The bacteria may be intrinsically resistantbecause of structural differences in the PBPs that are the target of thesedrugs. Furthermore, some bacteria can become resistant by the development ofhigh-molecular-weight PBPs that have decreased affinity for the antibiotics. Soaltered PBPs with decreased affinity for the antibiotics can lead to theirdrug-resistance.
Solutions:
1. Announceof prevention
The basic rule is to avoid using antibioticsunnecessarily. Although that"s a decision for doctors, patients who implorephysicians to treat viral diseases like the common cold with antibiotics arenot doing themselves any favors, since antibiotics are worthless againstviruses.
2. Takethe full prescribe course
Many people quit taking the drugs after thesymptoms of their infection have disappeared, but some partly-resistantmicrobes might remain. If you quit taking your meds at that point, you"reallowing the partly-resistant organisms to survive and multiply.
3. Bespecific
Use the most specific antibiotic possible.--"narrow-spectrum,"antibiotics will kill the offending bug without sparking resistance among otherbacteria living in the patient, as broader-spectrum drugs might.
4.Be logical
Use the common antibiotics first. If theywork, there will be no need to expose the bugs to more exotic drugs, whichserve as a second line of defense.
5.Reduce hospital transmitted infections
Kill the bugs before they get insidepatients. That can be done with ultraviolet lights, better sanitation, andputting patients with recalcitrant infections in isolation wards.
6.New drugs
Invent antibiotics that have new mechanismsfor killing microbes.
7.Reduce widespread use
Consider reducing the widespread use of antibioticsin animal feeds.
References:
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