Antibacterials Part 1 Flashcards
What is prontosil converted to? Why is this important?
Prontosil was not actually the compound affecting bacteria, the derivative sulfanilamide was the causative compound. Conveniently, prontosil is converted to sulfanilamide by the bacteria in the GI tract, not by
the agent being targeted. Sulfanilamide can then enter the blood stream and subsequently travel to different parts of the body where it can reach the site of infection. This is an example of a pro-drug: drug is given in the inactive form and is converted to the active form in the body. The concept of a prodrug has been used in many drug situations. Currently the concept is being used to more selectively target cancer cells. If you could find something that is present in cancerous cells, but absent in normal cells, that could alter an inactivedrug into the active form, then you could selectively kill those cells with the ability to convert it.
Describe the phases observed when bacteria are grown in culture. Why do these phases occur?
Bacteria grown in culture have 3 phases of growth. First is a lag phase:
bacteria were taken from a culture where they had previously reached the
stationary phase, basically non-growing, so there is going to be a lag phase before they are able to grow. They all of a sudden have access to excess nutrients,but it takes a while for them to take them up and incorporate them into biomolecules. After the lag they grow exponentially until eventually hitting the stationary phase. Stationary phase is a combination of running out of essential metabolites as well as producing toxic material, some of which may lower the pH of the media. And so theyll sit there until the waste is removed and they getmore nutrients.
How can one tell that sulfanilamides are bacteriostatic rather than bacteriocidal?
Sulfanilamide mimics the basic growth curve in that there is a lag and log phase, but it plateaus out at a lower number of bacteria that you acheive without the drug. This indicates that the sulfanilamide is not directly causing bacterial killing, basically the growth is stopped after a lag period of time.
Suggests that something is being depleted that the organisms need in order to grow.
History of sulfanilamides
Gerhard Domagk demonstrated in 1933 that prontosil protected mice and rabbits against lethal doses of Staphylococus and Streptococcus bacteria (Awarded Nobel prize in 1939)
Why should you not use a bacteriostatic drug if you have an immune deficiency?
Sulfanilamides target is dihydrofolate synthase. Dihydrofolate synthase is necessary to make thymidine. Sulfanilamides are bacteriostatic. If you have an immune deficiency, taking a bacteriostatic drug wont buy you much time. You need your immune system to wipe them out, so even if you stop them from growing for a period of time, once the drug is cleared from your system theyll start to proliferate again. This is assuming that other bacteria in your body have not eliminated/ outcompeted them. So dont use a bacteriostatic drug if you have an immune deficiency, use a bacteriocidal one. Sulfanilamide is a DNA synthesis inhibitor (thymidine is one of the four bases used to make DNA), so this presents a potential problem…because our cells also need to syntehsize thymidine to allow for DNA synthesis to occur.
What allows sulfa drugs to inhibit the growth of bacteria and not eukaryotic cells?
Bacteria must synthesize PABA in order to form dihydrofolate and eventually tetrahydrofolate to carry all of the needed synthesis out for thymidine. We do not have dihydrofolate synthase and so it wont affect us at least in terms
of this mechanism. We acquire our folate through diet, and in part through
bacteria that inhabit our gut (they die and release folate). One problem
with some antibiotics is that if you eliminate too many of the bacteria
that we get folate from, then unless you’re getting a sufficient amount of
folate in the diet, you may develop a folate deficiency and see effects in
a decrease in DNA synthesis and other biosynthetic pathways that require
folate.
How can it be beneficial to give a drug orally that is poorly absorbed in the gut?
Normally, when you a give a drug orally that is poorly absorbed in the gut, you don’t really think of that as very useful. However,when you have an infection in your colon, it could
actually be an advantage. So drugs listed to the top right that are very poorly absorbed (low to nonexistant half-life) can be used to treat GI and intestinal tract infections. Lets say however, that you have a skin
infection/ wound infection. Then a drug that is given topically is often useful such as sulfacetamide. Silver itself has antibacterial properties and is added to some sulfanilamides to create a combination effect
(2 antibacterialagents present). Generally silver is only included in topical ointments as it doesn’t readily get across membranes to be affective elsewhere.
What are some sulfanilamides that are absorbed and excreted rapidly?
Sulfisoxazole, sulfamethoxazole, and sulfadiazine. These can be used to treat systemic infections and can be taken orally.
What is a sulfanilamide that is poorly absorbed and is active in the bowel lumen?
Sulfasalazine
What are some sulfanilamides that are used topically?
Sulfacetamide and silver sulfadiazine.
What is a sulfanilamide that is long-acting?
Sulfadoxine
What are some side effects and issues with sulfa drugs?
Deficiency in white blood cells (leukopenia). Deficiency in platelets
(thrombocytopenia). Aplastic anemia, where bone marrow stope producing red
blood cell precursors. What causes these is not well understood. These fall under the category of side effects known as idiosyncratic reactions, meaning that we have no idea what causes them. Crystalurea, some of the compounds can fall out of solution in urine and form crystals. this can cause kidney damage, fortunately most sulfa drugs dont do this. Sulfa drugs bind to albumin, and will compete with albumin binding to oral hypoglycemics, or warfarin type drugs. Phenytoin will also compete with the P5450 isozymes that metabolize the sulfa drugs, so theres potential for drug-drug interactions. Additionally there are some allergic reactions that can occur: stevens-johnsons syndrome (blisters all over the body), toxic epidermal megalolysis, exfoliative dermatitis (skin sheds off the body).
What’s a genetic condition that can create problems when combined with sulfa drugs?
Genetic condition: Glucose-6-Phosphate Dehydrogenase deficiency. This enzyme is used in glycolysis and the pentose phosphate pathway. Problem comes with the pentose-phosphate pathway. Among the products produced in this pathway, is a reducing agent (NADPH). This product is especially important in our red blood cells. NADPH is used to reduce glutathione. So glutathione is very important in terms of overcoming oxidizing agent, so its a protective agent. The specific issue is that in red blood cells,
there is glutathione peroxidase which utilizes glutathione. Necessary for converting hydrogen peroxide to water. If there starts to become an accumulation of hydrogen peroxide in red blood cells, then hemoglobin starts to get damaged which subsequently leads to the formation of reactive oxygen species which work to create membrane damage. So individuals
with this defect dont express high enough levels of G6P which results in this chain of events leading to membrane damage, resulting in lysis of red blood cells giving whats called hemolytic anemia. So if you have this genetic condition and take sulfa drugs, theyll basically make the situation worse. The hemolytic anemia is only going on if you have a lot of oxidizing agents. Sulfa drugs are oxidizing agents so it depletes the already low level of glutathione. Favabeans should be avoided as well if you have the disease and can result in
death via the hemolytic anemia. Condition is sometimes referred to as favism.
What was the 1937 Elixir Sulfanilamide Incident?
- A company marketing sulfanilamide made an elixir containing the drug resulting in the poisoning and death of ~ 100 individuals
- The elixir consisting of sulfanilamide, raspberry syrup, and diethylglycol was marketed without testing by Massengil, the pharmaceutical manufacturer (the pharmacist who did this committed suicide)
- Led to the 1938 Food, Drug, and Cosmetic Act, which required that companies perform animal safety tests on drugs
What do sulfa drugs bear resemblance to and how does this dictate their MOA?
Sulfanilamides bear a resemblance to PABA. PABA is one of the building blocks in the biosynthetic pathway to forming tetrahydrofolate. Tetrahydrofolate is a major methyl group donor that is necessary for purine synthesis, generation of amino acids such as methionine, but most importantly, it is essential to forming the base thymidine, which is necessary to form ATP, which is necessary to power DNA synthesis. Given that sulfanilamide and PABA are sturcturally similar, it was easy to propose that sulfanilamide simply competes with PABA in the synthesis of tetrahydrofolate. However, it needed to be proven.
