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Antimicrobial Drugs

I. The term chemotherapy is usually associated with the treatment of cancer by anti-tumor drugs. This term, in fact, refers to the control of any disease using drugs. In the case of infectious disease, this involves the use of drugs that will kill or limit the growth of microorganisms. Up until the early part of this century no effective antimicrobial chemotherapeutic drugs existed. For such a drug to be effective, it must be able to kill or limit the growth of a microorganisms without severely affecting cells of the host. This is referred to as selective toxicity. For bacteria, differences in structural components (such as the cell wall, minor differences in the ribosomes and RNA polymerase) are usually what is "attacked" by the chemotherapeutic drug. In the case of those eukaryotic organisms that cause disease (fungi, protists and helminthes) along with those agents that are intracellular parasites (viruses and some bacteria) finding chemotherapeutic agents is much more difficult since the pathogens are within our cells and often using our own enzymes in their metabolic processes.

A. By 1910, Paul Ehrlich had developed a drug known as salvarsan that was able to limit the growth of the organism that causes syphilis. The problem with salvarsan was that it was only slightly more toxic for the microbe than for the host.

B. The big push for developing better chemotherapeutics was partially driven by the appalling death rate from infection suffered by soldiers during World War I. In the 1930's, a German chemist, Gerhard Domagk, developed a more selectively toxic compound derived from a synthetic dye.  This drug was known as protonsil (or protonsil rubrum).  Once internalized the drug is converted by the liver to a compound known as sulfanilamide. Sulfanilamide is a member of a class of compounds known as the sulfonamides commonly referred to as the sulfa drugs. In preparation for a war that might be approaching, the British needed also to develop effective chemotherapy. This led to the development of the first antibiotic.

1.  Nearly a decade earlier (the late 1920's), an English microbiologist named Alexander Fleming observed that a colony of the mold (Penicillium notatum) which had contaminated a petri dish of the bacteria  Staphylococcus aureus, inhibited the growth of Staphylococcus aureus. This inhibition he termed antibiosis. It would be ten years before the chemical responsible for this phenomena was exploited to make the first antibiotic, Penicillin. It should be noted that antibiotics are chemicals produced by living microorganisms to inhibit the growth of other microorganisms. Drugs like protonsil which are produced in the laboratory are referred to as synthetic drugs.

2. After the testing and widespread use of penicillin during WWII, the hunt for other antibiotics yielded a large number of other agents that could be used in treatment of bacterial infections.

II. By chemically modifying antibiotics, chemists were able to develop the semisynthetic drugs. These drugs start as antibiotics but by the addition of chemical groups, the characteristics of the antibiotic can be radically altered. Chemical modification of a naturally occurring drug is done for several reasons including changing the pharmokinetics of a drug, altering the spectrum of activity of a drug and circumventing the resistance that bacteria have developed to a drug. 

A. Pharmokinetics refer to the way the manner in which the drug is distributed in the body and the way the body eventually eliminates the drug.  By chemically modifying antibiotics the sites in the body where the drug reaches therapeutic levels can be altered. Similarly the time that the drug remains in the body can be increased (or decreased). 

B.  Different antibiotics (and synthetic drugs) are effective against different types of organisms. The range of organisms over which a drug exerts an effect is that drug's spectrum of activity. For some drugs this is an extremely narrow range while others will adversely affect most bacteria (broad spectrum drugs). Chemically altering narrow spectrum antibiotics has resulted in semisyntheitc drugs with extremely broad spectrums. 

III. As mentioned earlier, most the chemotherapeutic drugs that are effective against bacteria interrupt some metabolic activity that is unique to bacteria.  The way in which a drug affects microbes is referred to as the mode of action of that drug. In many cases the antimicrobial drug competes for access to the active site of an essential enzyme.  Once in the active site they bind and do not leave.  Thus the enzyme is inactivated. This is referred to as  competitive inhibition.

A.  Early antibiotics like penicillin and vancomycin acted by disrupting either the synthesis of peptidoglycan.   Lately, a group of drugs known as the cephalosporins have become the drug of choice in the treatment of many infections.  Cephalosporins, penicillin and all semi-synthetic derivatives of these antibiotics have a chemical structure known as a beta-lactam ring  and are commonly referred to as b-lactam antibiotics. The action of all b-lactam antibiotics involves the b-lactam ring fitting  into the active site of one of the enzymes involved in the formation of peptidoglycan.

1.  These antibiotics disrupt cell wall synthesis. Thus as cells are formed and begin to generate a cell wall the presence of these antibiotics  will result in weak and/or deformed cell walls.  Minor shifts in osmolarity can result in rupture of the cell.  This group of antibiotics exerts little or no effect on bacteria that are not rapidly growing.

2.  The original penicillins were generally more effective against the gram positive organism.  They exerted little or no effect on gram negative cells (the major exception to this was the effect that penicillin had on Neisseria gonorrhea, a gram negative organism).  In the case of most gram negative organisms, the lack of activity by penicillin  results from the barrier presented by the outer membrane of a gram negative cell and from differences in the enzymes involved in peptidoglycan synthesis.  The semisynthetic penicillins that came later are able to penetrate this outer membrane and bind with the peptidoglycan forming enzymes of the gram negative organism as well as those of the gram positive organism.  Ampicillin is slightly a modified form of  penicillin but is one of the broader spectrum antibiotics on the market.  In most cases if an antimicrobial drug ends in “-cillin” it is a semi-synthetic derivative of penicillin.

3. The initially isolated cephalosporins (first generation cephalosporins) were mainly effective against gram positive organisms. Chemical alteration of this antibiotic led to the production of second generation cephalosporins.  These drugs have a broader spectrum of activity. Second generation cephalosporins are effective against many gram negative organisms.  Further modification of cephalosporins led to third generation cephalosporins.  These drugs are notable in that they are highly effective against members of the genus Pseudomonas and against organisms that have developed resistance to penicillin or the other cephalosporins. Third generation cephalosporins show decreased effectiveness against many gram positive organisms

4. Vancomycin interferes with the synthesis of the cell wall but is not a b-lactam antibiotic Its interference with the synthesis of peptidoglycan involves blocking the action of enzymes involved in the synthesis of peptidoglycan that are different than those blocked by the beta-lactam antimicrobials.  Early preparations of this drug were contaminated with toxic materials that led to unwanted side effects.  Improved purification methods have yielded contaminate-free preparations of vancomycin that have little of the earlier side effects. This drug is most often used to treat  penicillin-resistant strains of  Staphylococcus aureus.

B. Several classes of drugs inhibit the cell's ability to synthesize the nucleotides needed in the synthesis of nucleic acids. This is accomplished by binding to the active sites of enzymes in the pathways involved in the production of these biochemicals. This competing for access to the active site is referred to as competitive inhibition. Once in the active site they bind and do not leave. Thus the enzyme is rendered inactive.

1. Sulfonamides (Sulfa drugs) inhibit the enzyme which converts para-aminobenzoic acid (PABA) into dihydrofolic acid. Dihydrofolic acid eventually will become the nitrogenous bases known as adenine and guanine. Blocking PABA conversion to dihydrofolic acid effectively halts synthesis of nucleotides.
2. Trimethoprim similarly inhibits synthesis of nucleotides by interrupting a second enzymatic reaction (conversion of dihydrofolic acid to tetrahydrofolic acid) in the pathway that leads to the synthesis of guanine and adenine.

C. All cells must be able to carry on protein synthesis thus all cells must have ribosomes. But the ribosome of the  procaryotic cell  differs slightly from that of the eukaryotic cell. This difference is the basis of action for several antibiotics which block translation in the procaryotic organism but have little or no effect on translation in the eukaryotic organism. These drugs include chloramphenicol, macrolides (erythromycin), aminoglycosides (streptomycin) and tetracycline.

D.  The peptide antibiotics are produced like all other peptides, through the action of ribosomes, mRNA, etc. Their mode of action involves binding to phospholipids and disrupting the integrity of the cell membrane. This results in "leaky" cells and leads to cell death. Polymyxin B is an example of this type of antibiotic. Because the phospholipid is found in both eukaryotic and procaryotic cells, this drug is highly toxic to the host.

E. The antibiotic rifampin (a derivative of the antibiotic rifamycin) inhibits the synthesis of mRNA. Differences in the RNA polymerase of procaryotic cells when compared with that of the eukaryotic cell allow this antimicrobial to selectively inhibit the action of procaryotic RNA polymerase, thus minimizing the toxicity of this drug. It is very effective in penetrating tissues and reaching the inside of the tubercles of tuberculosis. Consequently, it is used in controlling TB infections.

F. Quinolones are a class of antibiotics that inhibit the function of DNA gyrase.  In this way they interfere with a cell's ability to carryout semiconservative replication.  Levoquin is a commonly used quinolone.  Its name is derived from the fact that it is the "left-handed" or levo- stereoisomer.  The "right-handed" or dextro- form of the drug causes many unwanted side-effects.  Safe quinolone drugs were not available until methods for separating the levo from the dextro stereoisomer on an industrial scale were developed.    

IV. Microorganisms have incredible ability to adapt. Consequently, they have rapidly evolved resistance to the antimicrobial drugs. Furthermore, certain types of organisms are not harmed  by particular antimicrobials due to the intrinsic makeup of the organism (ex. most gram negative organisms do not allow  penicillin through their cell membrane).  In other cases, bacterial produce proteins that imbue them with resistance to antimicrobial drugs. Often the genes for the proteins that allow bacteria to survive in the presence of antimicrobial drugs are found on plasmids and can thus be readily transferred between organisms by conjugation. Such plasmids are referred to as R factors.

A. Development of resistance can occur through several ways.

1. Synthesis of enzymes that destroy the antibiotic is a fairly common mechanism. Much of the penicillin resistance that is observed is due to the production of enzymes which destroy the beta-lactam ring of the penicillin molecule. These enzymes are referred to as beta-lactamases.
2. Selection for bacteria that do not import the drug is also an important mechanism. For drugs that act upon ribosomes they must be transported into the cytoplasm. If a bacteria loses the ability to import the drug, the drug will stop having any effect on that organism.
3. Alteration in the enzyme against which the drug exerts its effect can lead to a development of resistance to that particular antimicrobial drug.   Alteration in the ribosome has allowed organisms to develop resistance to many of the aminoglycosides and erythromycin.
4. Use of alternative metabolic pathways allows the organism to synthesize needed materials using different enzymes than those interfered with by the antimicrobial. Much of the resistance to sulfa drugs is due to use of alternative pathways for the synthesis of folic acid.
5. Recently, proteins have been isolated that "pump" certain antimicrobial drugs out of the cytoplasm of the bacteria. These proteins reduce the amount of antimicrobial drug in the cytoplasm to the point at which the drug is not effective.

B. Development of resistance is a natural phenomenon. The rate at which resistance develops is influenced mainly by levels of usage of a drug. Over-prescribing of antimicrobials is one of the contributing factors in development of resistance. Improper usage of antimicrobials by the patient also allows for selection of those organisms that have attained partial resistance. Exposure of these organism to the same antibiotic at a later date will often lead to higher and higher levels of resistance to the drug by that  organism.

C. Once resistance to antimicrobial drugs has evolved, the genes for that resistance can be spread to other organisms through conjugation, transformation and transduction. In this manner pathogenic organisms can receive the genes that will make them resistant to the drugs we would like to use against them. It is hard to overstate the importance of limiting the spread of antibiotic resistance. To this end several measures must be taken including:

1. more prudent selection of the drug which will be prescribed so that newer drugs are not widely used,

2. full compliance of patients in taking the drug as prescribed

3. stopping the practice of "antibiotics on demand". It is estimated that 40-60% of the antimicrobial drugs which are prescribed are for viral illnesses.

Here are some links!!

Medical College of Wisconsin

A guide to chemotherapy used for some common infectious diseases.

Medical Microbiology Textbook , Antimicrobial Therapy

In-depth examination of  antimicrobial agents.  Very good!!

Grapes of Staph

More elementary discussion of the mode of action of common  antimicrobials.  This is similar to what you heard in class.


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