Dear students, already we have seen synthetic antifungal agents. So in this class we are going to see polyene antibiotics. So what are polyene antibiotics?
They are isolated from stryptomyces species and they are having conjugated double bonds in a macrocyclic lactone ring what is meant by conjugated double bonds that is altenate double bonds are there in macrocyclic lactone ring what is meant by macrocyclic large cyclic ring so that is called as macrocyclic and that is having lactone in the structure so it is a large cyclic lactone ring that is having conjugated double bond and it is isolated from stryptomyces species this Already we have seen macrocyclic ring, where we have seen, we have seen this under antibiotics, that is the macrolide. So what is the difference between that macrolide with this one? That macrolide antibiotics are antibacterial agents, whereas this polyenes, these macrocyclic rings are used as antifungal agents.
And while comparing with that macrolides, this would be larger and that is having conjugated double bonds. that is conjugated double bonds are present in this poly in antibiotics that's why these are called so poly in e no it is ending with in so what is the suffix for e so e no that is indicating presence of double bonds so polygons many double bonds more than two bonds more than two double bonds that's why these are called as poly in antibiotics so what is the difference between macrolides with this one while comparing with the macrolides these are larger and having conjugated system of double bonds that's why they are called as polyene antibiotics based on the size of this macrocyclic ring this polyene antibiotics are of two types one is a 26 membered ring polyenes another one is a 38 membered macro cycles example for this 26 membered ring polyene would be natamycin otherwise called as pimericin under 38 membered macro cycles Two examples are there. One is amphotericin B.
Another one is called nestatin. These are having a series of hydroxyl groups on the acid derived portion of the ring. So these are having many hydroxyl groups and glycosidically linked deoxyaminohexose that is called as mycosamine. So what are all present in the structure of polyenes already we have seen these are having conjugated conjugated system of double bond and that is present in a macrocyclic lactone ring so in the macrocyclic lactone ring it is having a series of functional groups they are hydroxyl growth so it is having series of hydroxyl groups so many hydroxyl groups are there and it is having a sugar that is called as the mycosamine so what uh what is that it is a deoxy amino hexose what is the type of the sugar what is the name of the sugar the name of the sugar is mycosamine what is the type it is a deoxy amino hexose and this one is a glycosidically linked to this macrolides that is a macrocyclic lactone ring the number of the double bonds in the macrocyclic ring differs also for natomizine already we have seen three examples no so one is natomizine that is the 26 membered one another two are amphotericin b and nistatin they are 38 membered already we have seen this Now, for Natamycin, that would be the smallest macrocycle and that is a pentayin. Pentayin means that is having only 5 double bonds.
So, Natamycin is the smallest macrocycle and that is a pentayin having only 5 double bonds. What about for Nystatin? That is a hexayin that is having 6 double bonds.
And what about Amphotericin B? That is a heptayin that is having 7 double bonds. So, Natamycin is having 5 double bonds. Statin is having 6 double bonds whereas amphotericin B is having 7 double bonds. The polyenes are no activity against bacteria, rickettsia or viruses.
So it is not active against bacteria, rickettsia or virus but they are highly potent broad spectrum antifungal agents. They are active against certain protozoa such as Leishmania species and they are effective against pathogenic yeast. molds and dermatophytes.
Low concentrations of the polyenes will inhibit some species like candida, cryptococcus, aspergillus, cephalosporium etc. But the use of the polyenes for the treatment of systemic infections would be limited because of three reasons. One is the toxicity Second, low water solubility and third one is the poor chemical stability. So because of these three reasons, they would be limited for the treatment of systemic infection.
So what are the three reasons? Toxicities of the drug, low water solubility and the poor chemical stability. Amphotericin B, I mean from that three, this amphotericin B is the only poly in that would be useful for the treatment of serious systemic infections. But that must be solubilized with a detergent. If it is used for the treatment of systemic infections, but that should be solubilized with a detergent.
The other polyenes are indicated only as the topical agents for superficial fungal infection. So, which is the only polyene that is used for the treatment of systemic infection? That is amphotericin B, but there may be one condition. What is that?
It must be solubilized with a detergent. So others are used for the treatment of superficial fungal infections as a topical agent. So the drug is a fungistatic at low concentration and fungicidal at high concentration.
So at low concentrations the polyenes bind to a membrane bound enzyme component such as ATPase. Now we will see the mechanism of action of this polyene antibiotics. Because of their three dimensional shape barrel like Non-polar structure capped by the polar group that is the sugar group they penetrate the fungal cell membrane and they are acting as a false membrane component. So what is the action? It is having three-dimensional shape a barrier like non-polar structure and it is having one sugar node that is capped by the sugar that will be the polar group because of that they penetrate the fungal cell membrane and acting as a false membrane component.
So this polyenes, so here we have seen they penetrate the fungal cell membrane and acting as a false membrane component. So because of that they are binding with the membrane sterol. So already we have seen this ergosterol in fungal cell membrane. So this polyenes will bind with the membrane sterol that is the ergosterol that is present in fungal cell membrane. Because of the binding it produce this.
produces an aggregate and forms a transmembrane channel. Intramolecular hydrogen bonding interactions among the hydroxyl group, carboxyl and amino groups stabilize the channel in its open form and altering the cell membrane permeability. Because of the alteration in the cell membrane permeability, the cytoplasmic contents would be leaked out, especially mainly the potassium that would be leaked out. and there may be cell rupture and finally leads to cell death so what is the mechanism of action the polyenes will bind with the ergosterol that is present in fungal cell membrane and forms an aggregate that aggregate will form a transmembrane channel between this i mean within the structure there may be intramolecular hydrogen bonding interactions between the substituents that is hydroxyl group carboxyl group and amino groups they stabilize the channel in its open form And they are altering the cell membrane permeability.
So the cytoplasmic contents would be leaked out especially the potassium. There may be a cell rupture and finally that leads to cell death. So that's all about polyene antibiotics. Next class we will see the drugs and the polyene antibiotics.