Wednesday, April 23, 2014

Old champions get new help


     So often has been antibiotic resistance been talked about in this page, that it needs no introduction. There is a huge list of antibiotics that is currently in research. There are all sorts of chemicals, that has been investigated. It is now almost impossible to keep track of the growing list (I probably have even lost the count). The whole story of magic medicine bullet (Antibiotics I mean), has started from the discovery of penicillin (Not by Alexander Fleming, Read the story here). It was the champion till drug resistance began to stage a threat. Today, I can hardly recall infections, where penicillin is the only drug that is required. We now talk about terms like Multi drug, Pan drug resistance, Superbugs, and even drug dependence.

     Before I talk about the paper in question, it is important to look at how penicillin acts. Penicillin is a member of a huge family of chemicals, called as β- lactam. The cell wall holds a very high pressure inside it. Second important thing that is not easily realized is that the cell wall is not a permanent structure. The bacteria continuously synthesizes new layers. This makes an active bacteria like Staphylococcus, cell wall extremely sensitive. Failure to synthesize new peptidoglycan continuously, and the cell goes like woosh....burst, due to a very high internal pressure. Peptidoglycan synthesis involves making NAG-NAM links which are cross linked by peptides. This linkage is what provides the stability. The cross linking is by the action of an enzyme called as transpeptidase.

Fig 1: Transpeptidase inhibited by Penicillin.
     DD transpeptidase (D-alanyl-D-alanine transpeptidase), is the key enzyme. Its natural substrate is D-Ala-D-Ala which is competitively inhibited by the β- lactam. They connect the D-center of meso-diamino-pimelic acid in position 3 (meso-DAP3) of one side chain to D-alanine in position 4 (D-ALA4) of an adjacent side chain and are therefore called DD-peptidoglycan-transpeptidases. Look at figure 1 which is a comparison between the D-Ala-D-Ala and the β lactam. In many textbooks you will read "Penicillin binds to Penicillin binding proteins (PBPs)". That is true. Point is, when the structure of DD transpeptidase is found it gets called as PBPs for obvious reason.

      The bacteria evolved tricks. They made the DD transpeptidase inaccessible, or made enzymes to break the antibiotic itself. To evade the enzyme protective agents such as Betal lactamase inhibitors are used in what is called as a BL/BLI combinations. More recently Non β-lactam/β-lactamase inhibitor avibactam has been proven highly affective (Read my previous post on this here). By using improved β-lactamase inhibitors, we can use old antibiotics like penicillin to do the job again.

     One more chemical now makes the same headlines. Chuanbing Tang states "Instead of developing new antibiotics, here we ask the question, 'can we recycle the old antibiotics?' " he said. "With traditional antibiotics like penicillin G, amoxicillin, ampicillin and so on, can we give them new life?" In their new report, published in JACS, a metallopolymer was shown to do a similar job. They prepared a cobaltocenium metallopolymer that greatly slowed the destructiveness of beta-lactamase on nitrocefin (Model beta-lactam molecule). Based on the results, they further elaborated its effectiveness on HA-MRSA. But here's the punch point. The metallopolymer alone demonstrated antimicrobial properties, lysing bacterial cells.

     Similar approaches are gaining more popularity. This approach is highly attractive, for it helps us to bring back the older classics into action, without having to invent a bunch of new ones. Let me cite one more example which is a bit of older concept.

Table 1: Efflux pump families.
     One of the mechanisms by which, bacteria avoids antibiotic action, is by pumping out the antibiotic using efflux pumps. Years of research has been devoted in developing Efflux pump Inhibitors (EPI). Efflux pumps comes in a variety of types. They are classified into families- Perhaps the best studied among them is L-Phe-L-Arg-β-naphthylamide or more commonly known as PAβN. This compound interferes with members of the RND family. Publications have explored to look at similar concepts. For example, chemicals are developed to try and get the drug inside the bacterial cell easily, using hydrophobic chemicals (Link).

    My conclusions are simpler. Yes we need new class of drugs with novel mechanisms. Antibiotic development is going to be a ever running field in medicine, cause it is hard to beat evolution. But by making chemicals, that can rearm the older champions, we have a better edge.
Zhang J., Chen Y.P., Miller K.P., Ganewatta M.S., Bam M., Yan Y., Nagarkatti M., Decho A.W. & Tang C. (2014). Antimicrobial Metallopolymers and Their Bioconjugates with Conventional Antibiotics against Multidrug-Resistant Bacteria., Journal of the American Chemical Society, PMID:

The efflux inhibitor phenylalanine-arginine beta-naphthylamide (PAβN) permeabilizes the outer membrane of gram-negative bacteria., PloS one, 8(3): e60666. PMID: 23544160

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