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Antimicrobial Drugs

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Antimicrobial drugs



Welcome back to this course on Organic Chemistry in Biology and Drug Development.

Last time, we have discussed, the chemistry of hypertension and what is the humoral

cause for hypertension and mechanism for the production of angiotensin 2.

And then we have discussed, how the drugs like captopril, enalapril and other these type

of drugs we were discovered based on the drug design principle; based on the mapping

of the active site and ultimately we got to know that how this drug can be designed

rationally. In fact, captopril is known as the first rationally designed drug.

(Refer Slide Time: 01:30)



Today we will change the topic and go to a very important one which is affecting us all

over the world, hypertension is also like that, but hypertension is usually affecting the

more aged people than the younger ones. However, these antimicrobial drugs are very

important, because throughout our life, at some point or other, starting from the

childhood, we suffer from infections that are caused by small microorganisms,

microorganisms are small, as the name suggests.



And these microorganisms include bacteria, virus, fungus all these. So, we will discuss

the antimicrobial drugs and their chemistry and how actually they evolved to save the

human lives.

(Refer Slide Time: 02:43)



So, antimicrobial drugs are basically chemicals which work against infections caused by

a microorganism. Now, every topic of research has a history behind it. So, drug

discovery process especially the antimicrobial agents’ related research has an illustrious

history behind it. First it was Louis Pasteur, he believed in one idea that one

microorganism survives against the attack of other microorganisms by producing some

chemicals.

It is like the survival strategy of our country that we produce different weapons or

procure different weapons and that is done to protect our own country against the

invaders. Similarly, in the bacterial world, one bacteria wants to predominate on the

other. So, the bacteria has adopted a mechanism by which they produce molecules

surrounding them and these molecules basically can kill other microbes surrounding it,

so that is the different survival mechanism of a microorganism like bacteria.

So that was Pasteur’s theory. However, when Pasteur attempted this, after isolating

some of these chemicals; he found that these are also toxics against humans. And if they

are also toxic against humans that means, they are basically useless compounds. So,

Pasteur’s theory remained as a theory, it was never practically implemented.



Now, in the year about 1900, another a scientist whose name was Paul Ehrlich was a first

one to believe that it is possible to develop chemotherapeutic agents in fact, the term

chemotherapy was coined by Paul Ehrlich.

So, Paul Ehrlich thought that it is possible to develop chemicals which will if taken

inside the body, then it will target the causative agent for the infection that means; if I am

suffering from any bacterial infection, then Ehrlich believed that there is a possibility

that you can design chemicals which if it is ingested, then that will not touch the host

machinery, but it will go and attack the foreign organism and then it will kill that and he

termed those chemicals as magic bullets.

So, magic bullets are nothing but chemicals, but it is why it is called magic? Because it it

does not affect the host, only affects the microorganism which is the causative agents for

the infection. So, these are called like bullets, like bullets you target a particular person

and then you kill that person. Now, in the body, you are not seeing where these bacteria

are, but it is possible to create magic bullets which will find the bacteria and kill it, so

that was his theory and these magic bullets are nothing but the he called the

chemotherapeutic agents.

So, he prepared different compounds, several compounds, 1000s of compounds were

made on those days and he along the Japanese scientist S. Hata found that this compound

number 606 was a very good antibacterial agent. Every compound had a number. And

commercially it was named as Salvarsan.

Salvarsan is the first known antibacterial agent, it is an arsenic based compound. Ehrlich

was awarded the Noble Prize in physiology and medicine because of his discovery of

Salvarsan that was the compound number 606.

And then subsequently in our country, Sir U.N. Bramhachary in Calcutta, discovered a

molecule which was called urea stibamine, which was an antimony (Sb) based. It was

well known those days that arsenic, antimony and bismuth are having antimicrobial

activity. So, people were starting to make these arsenic based compounds, antimony

based compounds and bismuth based compounds. In fact, all these three are utilized to

develop molecules which are drugs.



So, Salvarsan is an arsenic based compound and U.N. Bramhachary’s compound was

antimony based compound, this was an antibiotic not an antibacterial agent, because

there is a difference in antibiotic and antibacterial; I will tell you later. It treated a deadly

disease called syphilis, which was untreatable in those days.

The antimony based compound, this urea stibiamine, was utilized for treatment of black

fever, which in Bengali it is called kala azar. So, these are the initial developments in the

history of the antimicrobial drug discovery. Aspirin was discovered in the late 19th

century, so this is early part of 19th century.

And however, since these are metal based compounds, these were later on found to be

very toxic. So, apart from their beneficial action, they also have extreme toxicity. So, this

compound containing arsenic, Salvarsan is now no longer used because of its toxicity.

So, people started to look for different compounds. So, people although were killed of

syphilis, but they might be also killed by the toxicity of the arsenic based compound,

which is not desirable.

(Refer Slide Time: 10:52)



In 1928 when Fleming discovered the penicillin and exactly what happened that Fleming

had all these petri dishes, because antibacterial activities are determined by taking a

covered plate like what is called a petri dish. And you grow bacteria inside the dish and

you see the effect of different chemicals on the growth of the bacteria.



So, what Fleming observed? Fleming observed that one of his plates which was lying on

his bench for quite some time, because Fleming went for a holiday and 2 weeks later he

came back and without cleaning his petri dishes. So, he found one of his petri dish, he

looked at it and he found there is a growth of a fungus and around the fungus there is no

growth of any bacteria, this is a clear zone.

So, the bacteria were growing like this, because wherever there is a haziness that

indicates that bacteria is growing, but around this fungal mold, no bacteria can grow. So,

Fleming immediately realized, because he had a brilliant mind; he immediately realized

the potential of this mold. And interestingly that Fleming was working on the first floor

of the Queen’s Mary hospital.

And in the ground floor there was another colleague of him who was working with

different fungal strains and one of them was penicillium notatum that is the fungus, they

flew from the lab at the ground floor, went out of the window and finally, came through

the window of Flemings lab and it is just extreme sheer luck that the fungus went inside

the petri dish.

Because when you put the bacteria you have to open the petri dish and then after

spreading the bacteria, you close the lid; so that time fungus went inside the petri dish.

So, there are many stories everything. This is a serendipitous observation that is true, but

other people might have just washed this plate, but Fleming while checking all the plates,

he found that the plate which he was going to wash clean an autoclave, but he found this

miraculous observation and that gave the birth that is the birth of penicillin.

Then Fleming tried to grow this penicillium notatum fungus in flask, tried to isolate the

compound that means, the compound which is secreted outside this fungus, he tried to

isolate. He named the active compound without isolating it as penicillin, because it is

being produced by penicillium fungus and, but he could not isolate penicillin.

But he found that the crude extract of the fermentation of this penicillium fungus, if it is

grown and the filtrate is extracted, that filtrate had a lot of anti-bacterial activity; and but

he could not isolate it, so it had along with that active compound, it had other compounds

in it. He tried to work on mice that what is the toxicity level, you know all drugs need to

be shown that they are not toxic.



So, toxicological affect was fine, but because the active compound was present in tiny

amount and he wanted to isolate it, then he found that it is very unstable; he could never

isolate the penicillin, so he gave up the research. Just publishing two results; one in

British general of pathology and another publication later on in 1932, the first one is

1929 and then the 32, so these two publications were forgotten by the scientific world,

but later on it was two chemists in Oxford University, Howard Florey and Chain.

In 1939, they again went back and took the fungus from Fleming’s laboratory, met

Fleming, got the fungus and then grew it and then they isolated the penicillin. And tried

to determine its structure; some proposal was there that this is the structure, but finally

the structure was confirmed by Dorothy Hodgkins, the famous women crystallographer

in oxford. So, she finally proved the structure of penicillin, so that is the story and that is

the beginning of the antibiotic era.

Now, let me see what the difference between antibacterial agent and antibiotic is.

Antibiotics are compounds which are produced by microorganisms for their own benefit

and for their own survival to kill other surrounding organisms. So, antibiotics are

produced from microorganisms, whereas antibacterial agents are a broad class of

compounds. Any compound or any chemical which is having a power of destroying any

microorganism that is called antimicrobial; if it is bacteria, it is called an antibacterial

agent.

However, the general term should be antimicrobial agents, because antimicrobial will

include everything antiviral, antibacterial, antifungal, ok. So, this is the difference, so

basically antibiotic are isolated or they are produced by microorganisms. So, we do not

have to do much, we just isolate and grow the microorganism and start isolating the

active compound.



(Refer Slide Time: 18:00)



And there are many compounds which are in the market, they are all antibiotics. Now, let

us again just quickly revisit chemotherapy; basically the use of drugs that treat a disease.

And a drug that kills harmful microbes without damaging the host; see chemotherapy

means that it has got a selective toxicity; all compounds are not branded as

chemotherapeutic agents, if they have a high toxicity.

It’s only that chemotherapeutic agents not only treat the disease, but at the same time, it

should have less toxicity, less toxicity in the animal or human where it is being

prescribed.



(Refer Slide Time: 18:54)



It is again the same thing, I just already told what is an antibiotic; chemicals produced by

a microorganisms that kills or inhibits the growth of another microorganism. And

antimicrobial agents is a basically a chemical that kills or inhibits the growth of

microorganisms. So, I can say that all antibiotics belong to the class of antimicrobial

agent, but all antimicrobial agents are not antibiotics, because some could be synthetic

compounds.

(Refer Slide Time: 19:20)



Now, these are some of the different antibiotics that have been isolated from different

microorganism sources. I will say this penicillin, I have already told you that it has been

isolated from penicillium notatum. Griseofulvin is an antifungal compound, which is

isolated from another penicillium sources. Cephalosporin is a compound which is

isolated from cephalosporium species; gentamicin these are very well known

streptomycin, erythromycin, and chloramphenicol means Chloromycetin, and then

amphotericin B. And interestingly many of these are associated with Noble Prize

winning work. So, these are whole lot of compounds that have been isolated from

microorganisms and there is no end to it, because if you today want to enter into this

field antibiotic, what you have to do? You have to see a new microorganism, you have to

isolate and then see what type of chemicals it is generating.

However, it is hard to beat the multinational pharmaceutical companies, because they are

having a collection a huge library of microorganisms and then try to see what type of

compounds they produce. So, usually this is in the domain of pharmaceutical industry.

(Refer Slide Time: 21:04)



And not academic, academically it is very difficult, because you can only touch a few of

the microorganism, but this is not the way, this is the same thing like combinatorial

library of different compounds gives you a possibility of identifying the hit quickly.

Similarly, a common library of different strains has a better chance of getting a new



antibiotic compound. These are some of the spectrum of activity of the antibiotics and

other antimicrobial drugs.

There are different agents that cause diseases, like mycobacteria which is the causative

agent of tuberculosis and leprosy. Then you have prokaryotic bacteria; beating the

prokaryotes you have gram negative and gram positive that is the gram sensitivity to

gram reaction. Then you have there are other types of chlamydia, that could be the fungi

means fungal infections, which are actually eukaryotes that is the higher organisms;

protozoa in protozoa is the malaria one.

Then helminth, helminths mean actually related to people suffering from this worm (tape

worm) infection. So, these are little bit longer in one direction and then you have viruses.

So, this is the spectrum of different micro different organisms that we suffer from. No

antibiotic is effective against all the microbes. It is not that you have one antibiotic that is

going to kill all these, from fungi to virus to mycobacteria, which is not possible.

Mycobacteria that is tuberculosis drug, one of the earliest drug in streptomycin. For gram

positive infection, penicillin was the drug of choice, then you have mefloquine that is for

malaria. You have a tetracycline which has got a broad spectrum. You know, narrow

spectrum antibiotic, broad spectrum antibiotic. Broad spectrum means which actually

covers many of these microbes, like tetracycline is a broad spectrum antibiotic, and the

penicillin.

Some of the penicillin are quite narrow spectrum, they just kill gram positive bacteria,

but we will cover that; there are now different types of penicillins which can also kill

gram negative bacteria, but gram positives are the real targets of penicillins. Then

isoniazid is a synthetic compound that works against tuberculosis, so that is the

spectrum. So, when we talk about antimicrobial chemistry, you have to touch these

prokaryotes infections and the eukaryotes infection and the viruses.



(Refer Slide Time: 24:29)



But we cannot actually cover all these in this course; we will just take some examples

which became the land mark in discovery of antibiotics. Now, mechanisms of

antimicrobial action; remember microbes have a life, so they have a life cycle and they

also utilize some of the processes that are also in-built and also going on in our body.

However, there is a difference, there are some differences between the enzyme systems

in the microbes vis-a-vis the humans.

Like bacteria have their own enzymes, which is not present in the host; host means I

mean the animal, the human, etcetera. Like cell wall formation, we will talk about what

is this cell wall; that means in bacterial cell there is a wall surrounding the cytosol that

means, whatever the components inside that is protected by the wall. Then protein

synthesis, we also have protein synthesis, we have already read this replication,

transcription and translation.

However, their enzymes might be slightly different from the enzymes that we have, and

if that be the case then you can exploit that difference. Remember when we talked about

the folic acid chemistry, we encountered an enzyme which is called dihydrofolate

reductase, this is present in bacteria, this is also present in human, but the dihydrofolate

reductase has different from in a microorganism versus the human. So, you can

selectively target the DHFR of bacteria.



DNA replication, see these are all processes which are common to the host; RNA

synthesis, transcription and the DNA replication, this is translation and synthesis of

essential metabolites. However, these can be the targets for devising an antimicrobial

agent. And the reason is that I said that although some of the enzyme systems are

common or processes are common, but there is a difference in the enzyme structure,

primary structure that means the amino acid and finally, the tertiary structure is also

different. So, you can exploit that difference

(Refer Slide Time: 26:53)



I think we will talk about these that how you can develop antiviral compounds,

antifungal and but this is very important. Whatever may be the target, the more similar

the pathogen, you are going to have more side effects and if the similarity is less, then

you will have less side effects and if there is no similarity, then you can expect that there

is very few side effects. Pathogen means the microorganism which is causing the

infection to the host body. In fact, penicillin is one of them that it has got extremely less

side effect, because if targets an enzyme which is not present in the human system, it is

not required in the human system.



(Refer Slide Time: 27:53)



Now, this is a schematic diagram, I told you what are the targets earlier, but this diagram

makes it little bit easier to understand that; this is the bacterial cell. And in the bacterial

cell there is this DNA and you have this transcription process mRNA, mRNA goes to

protein. The protein makes different small molecules, which are essential for the

survival. Now, where you can target, which can be the target for your drug discovery

process which are antimicrobial agents.

So, one is cell wall, because the cell wall is not present in the human cell. The human

cell is protected by what is called a membrane, a lipid membrane inhuman cell. In the

bacterial cell, apart from the lipid membrane, outside there is coat which is a very rigid

type of system and that coat is extremely important, because inside the bacterial cell, the

osmotic pressure is very high.

If the osmotic pressure is very high so that means, they are trying to go out. And so

outside osmotic pressure is low that means, when I put the cell in a biological medium,

outside the osmotic pressure is low, inside it is high. So, the water from outside wants to

enter into the cell. If water goes here, then is has to swell, because it has to accommodate

the water and there is no space; already it has got a lot of cytosolic material inside which

creates this high pressure. So, as water goes inside, it swells and then it bursts.

But the question is how water will go inside, so you create cavities that means, you make

molecules which will not allow the bacteria to form this cell wall. So, one good target is



cell wall and this cell wall humans does not have. So, cell wall synthesizing enzymes can

be very good targets for antibacterial agents. Then you have inhibition of protein

synthesis, so there are molecules like chloramphenicol, erythromycin, tetracycline,

streptomycin, they stop the translation process.

This cell wall is inhibited by penicillin, cephalosporins, bacitracin and vancomycin, very

important life-saving antibacterial agents. Then you can stop the bacterial transcription

process using the quinolones. Like you must have heard of ciprofloxacin, norfloxacin or

rifampin; that is again a tuberculosis drug, they stop the transcription process.

So, you can stop the production of mRNA by these quinolones, you can stop the

translation process by chloramphenicol, erythromycin etcetera. You can stop these

enzyme activities and hence stop making of important small molecules, like your folic

acid; remember sulfonamide is a PABA analogue.

And then trimethoprim is dihydrofolate reductase inhibitory in bacteria, so all these are

the targets. Bacterial cell wall, translation machinery, transcription and then you can also

target functional aspect where the protein which synthesizes different small molecules, is

inhibited. Dihydrofolate reductase was one example.

(Refer Slide Time: 32:07)



These are some of the structures which are isolated from the microorganisms. This is the

structure general structure of penicillin, see these structures; only similarity is between



the cephalosporins and the penicillin, but other structures are entirely different, this is

called rifampicin. And this is what is called tetracycline, you do not have to remember

the structures; my only intension is to show the variety of structures that these

microorganisms make including stereochemistry, everything is very stereospecific. This

is your ciprofloxacin and this is the chloramphenicol.

Apart from that, there are other molecules which are having different type of structures.

We are going to cover penicillin, we are going to cover cephalosporin, they come

together and we will also discuss some of the mechanisms of possibly chloramphenicol if

time permits.

Another term which has to be made clear is bacteriostatic and bactericidal. What is

bacteriostatic? Bacteriostatic is basically that if somebody suffering from some bacterial

infection and you add some chemicals some drugs, which stops the further growth of the

bacteria.

Like if a bacteria is already there, say 100 bacterial cells are inside my body, now what

they want to do? They want to divide; 100 will be into 200, then 200 will be 400, but for

the division to occur you have to utilize the machinery of replication, transcription, and

translation. Now, there are molecules like chloramphenicol which actually stops the

protein synthesis by inhibiting the translation machinery.

So, what will happen, the existing cells will remain, because they are already matured,

but when they try to divide that is not possible, that means, I will have this 100 bacterial

cells, I will not kill them, but I will not allow them to grow; so that is what is called

bacteriostatic that means, the bacterial population remains the same.

But then the question is how do I cure myself? Because if the bacteria does not grow,

that gives enough time for the body to make antibodies and then antibodies ultimately

take care of this whatever microorganisms are there; so that is bacteriostatic. On the

other hand, compounds which are called bactericidal in nature; bactericidal means they

go and kill the existing bacteria that means, the 100 bacterias will go to almost 0; so you

can see the difference.

So you are killing the bacteria with bactericidal agent; and penicillin is one example

which kills the bacteria and bacteriostatic is which does not kill the bacteria, but stops



the growth; both are antibacterial agents. But definitely if somebody has very weak

immunity, like somebody may be suffering from HIV infection, HIV is a viral infection

which ultimately attacks our immune cells and breaks down the immunity.

So, if anyone is suffering from HIV, bacteriostatic will never work, because he does not

have the immunity; so how can he take care of the remaining population of bacteria.

Even in case of transplantation, say kidney transplantation, your external organ, that

foreign kidney is given from the donor to the acceptor.

However, since it is not the part of the body system from the very beginning, so the body

thinks that it is a foreign agent and whenever body thinks something is foreign it

generates antibody. And then that means, there is a immune response and that rejects the

kidney; so there are many cases where the kidney transplantation is not successful,

because there the body does not accept the foreign kidney as its own.

So, what it usually practiced that at that point of kidney donation, you lower the

immunity of the body, practically to a very low level. And then you do the

transplantation. So, at that point, you slowly increase the immunity, see immunity was

very low slowly you increase the immunity and ultimately say after 2 to after 3 months, 4

months the body thinks that it is my own material. So, at that time if there is an infection,

you cannot treat that person with bacteriostatic drug, you have to give bactericidal ok, so

that is an important difference I told you.

I think in the next session, we are going to start with the chemistry of penicillin. So, it is

a very background introductory remark of antimicrobial compounds and then we will

slowly go to the actual drugs, their mechanisms, their discovery and all these things.

Thank you.