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Antimicrobial Drugs.

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1 Antimicrobial Drugs

2 Terminology Chemotherapeutic agents: Drugs to treat a disease
Antimicrobial drugs: Interfere with the growth of microbes within a host Antibiotic: Substance produced by a microbe that inhibits another microbe Selective toxicity: A drug that kills harmful microbes without damaging the host Chemotherapy drugs that act against a disease: any disease: insulin, antihypertensive drugs and antimicrobial drugs.

3 A Look Back Began in 1909 with Paul Ehrlich
Arsenic compound for treatment of syphilis Salvarsan 1929 – Fleming discovered penicillin, produced by Penicillium mold. Coined term antibiotic 1932 – Gerhard Domagk discovered sulfanilamide First to use agent to treat wide array of bacterial infecti0ns. Prontosil: red dye The idea of chemotherapy was the brainchild of Paul Ehrlich, a German scientist, who in the 20th century predicted that chemotherapeutic agents could be used to treat diseases caused by microorganisms. Finding a chemotherapeutic agent to kill a pathogenic microorganism wasn’t difficult, but chemotherapeutic agents also harmed and even killed host cells. This proved a major hurdle. A break through in 1928 when Alexander Fleming was growing S aureus in a petri dish. A colony of mold contaminated the dish surrounded the S aureus and prevented it from growing. The mold was penicillium notatum and the active compound Fleming named penicillin. It took roughly tens years from flemings discovery before the first clinical trials were successful. Wasn’t used in humans until 1941

4 Completely synthesized in a lab
Antibiotics Naturally produced antimicrobial agent Semi-synthetics Chemically altered antibiotics that are more effective than naturally occurring ones Synthetics Completely synthesized in a lab Many of the antibiotics in use today are produced from Streptomyces (bacteria that live in soil) Other antibiotics come from the genus Bacillus and from cephalosporium and penicillium both of which are mold

5 Action of Antimicrobials
Narrowspectrum: An agent that works against a single Gram negative, Gram positive, or a few organisms Broadspectrum: An agent that is effective against a wide variety of Gram positive and Gram negative organisms Bacteriacidal: An agent that kills the organisms Bacteriostatic: An agent that temporarily inhibits the growth of the organism long enough for the body’s defense mechanism to take over A major contributing factor to whether an antimicrobial is broadspectrum or narrowspectrum has to do with the ability of the antimicrobial to pass into the cell through the LPS of the gram negative through porins water filled pores and so whether a drug is hydrophilic or hydrophobic will have a big impact on the activity of the drug

6 The Action of Antimicrobial Drugs
Figure 20.2

7 The Action of Antimicrobial Drugs

8 Inhibitors of Cell Wall Synthesis
[INSERT FIGURE 10.3a-b] Recall that the cell wall regulates what exits and enters the cell and thus acts as a barrier. Protects a cell from the effects of osmotic pressure. Major structural component of a bacterial cell wall is its peptidoglycan layer. PTG is a huge macromolecule composed of polysaccharide chain of alternating N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) molecules that are cross-linked by short peptide chains extending between NAM subunits. The most common antibacterial agents act by preventing the cross-linkage of NAM subunits. Most prominent among these drugs are beta-lactams such as penicillin and cephalosporins

9 Inhibitors of Cell Wall Synthesis
Penicillin Selectively toxic Bacteriocidal Mechanism of Action (MOA) Competitively bind with transpeptidase (penicillin binding protein) Inhibits cross-linking of peptidylglycan Cell wall synthesis is arrested and the bacteria dies LPS PTG CM Gram negative Recall that both gram positive and gram negative bacteria possess peptidoglycan in their cell walls. These are composed of repeating dissaccharide subunits cross-linked with peptide chains. This cross linking is catalyzed by the enzyme transpeptidase. When introduced during WWII, penicillins were the miracle drug and were instantly put to work to treat combat infections. However early penicillins were only effective against Gram positive organismsPenicillin is a competitively inhibits transpeptidase and cell wall synthesis is arrested, the cell dies. Transpeptidase is also called penicillin binding protein More effective against gram positive than gram negative The enzyme transpeptidase mistakenly accepts the penicillin molecule as a substrate instead of peptidoglycan components. This renders transpeptidase inactive and thus the cell wall cannot be made or repaired. PTG CM Gram positive

10 Penicillin-Family Antibiotics
Amoxicillin Ampicillin Keflex Ceclor Cefzil Vantin Azactam Penicillin G is the original G-man of penicillins usually given IM or IV many organisms have now developed resistance to this form. Pcn V is an oral form Aminopenicillins (ampicillin and amoxicillin) is able to penetrate the outer wall of gram negative bacteria and better binding to the transpeptidase. However are still inhibited by penicillinase Penicillinase resistant penicillins: methicillin, nafcillin, and oxacillin are penicillinase resistant drugs that kill S aureus. Use of methicillin in USA DC’d because of nephritis. Antipseudomonal penicillins has expanded gram-negative rod coverage (pseudomonas aeruginosa) cephalosporins there are more than 20 different kinds. New basement makes beta lactam ring much more resistant to beta lactamases (but now cephalosporinases) A new R group side chain allows lots of lab manipulation Three generations division is based on their activity against gram negative and gram positive organisms First generation, second generation, third generation Cephalosporins 2nd, 3rd, and 4th generations more effective against gram-negatives

11 Resistance to Beta-Lactam Antibiotics
Bacteria defend themselves from the penicillin family in four ways Alter porins Gm + and Gm- possess beta-lactamase enzymes that cleave beta-lactam ring Penicillinase Alter structure of transpeptidase so antibiotics can’t bind Methicillin-resistant Staphylococcus aureus (MRSA) Gm + and Gm - may develop the ability to actively pump out beta-lactam before it binds to the transpeptidase Alter porins Gram-negative bacteria have a LPS layer outside of PTG layer of cell wall Porins are small pores in the outer LPS layer

12 Penicillinase: The Bacterial Answer to PCN

13 Beta-lactamase Inhibitors
These enzymes are inhibitors of beta-lactamase They are given in combination with penicillins to create a beta-lactamase resistant combination Clavulanic acid Amoxicillin and clavulanic acid: Augmentin Sulbactam Ampicillin and sulbactam: Unasyn Tazobactam Piperacillin and tazobactam: Zosyn A type of beta lactamase is penicillinase so these drugs block the bacteria’s ability to destroy the beta lactam ring of penicillins

14 Inhibitors of Cell Wall Synthesis
Bacitracin Inhibits lipid carrier, bactoprenol Prevents transport of NAM subunits through cell wall Effective as a topical treatment against Gram-positives Staphylococci Streptococci Vancomycin Glycopeptide derived from Streptomyces Prevents insertion of NAMs and NAGs into PTG wall Important "last line" against antibiotic resistant S. aureus In addition to the penicillin family other antibiotics are also effective inhibitors of cell wall synthesis Bacitracin is a polypeptide antibiotic (name comes from the organism Bacillus was isolated from a wound of a girl named Tracy) MOA is different from pcn acts by inhibiting the linear strands of PTG Vancomycin was derived from streptomyces found in the jungles of Borneo, narrow spectrum of activity against gram positive. Vancomycin never became first line treatment for Staphylococcus aureus for several reasons: The drug must be given intravenously, because it is not absorbed orally. β-lactamase-resistant semi-synthetic penicillins such as methicillin (and its successors, nafcillin and cloxacillin) were subsequently developed. Early trials using early impure forms of vancomycin ("Mississippi mud") which were found to be toxic to the ears and to the kidneys;[3] these findings led to vancomycin being relegated to the position of a drug of last resort.

15 Inhibitors of Cell Wall Synthesis
Members of the genus Mycobacterium have an atypical cell wall Contain mycolic acid Acid-fast stain Cause leprosy and tuberculosis Antimycobacterium antibiotics Isoniazid (INH) Inhibits mycolic acid synthesis Inhibits the enzyme, fatty acid synthase Drug of choice, generally used in combination with rifampin and ethambutol Because they don’t have typical bacterial walls (they don’t have PTG but rather incorporate mycolic acid into their walls) mycobacterium are not going to be sensitive to the PCNs instead other antibiotics are used to treat these pathogens Both Isoziazid and ethambutal inhibit cell wall synthesis Ethambutol is not the drug of choice because of its weak activity and generally is used in combo with INH to minimize drug resistance

16 Antifungal Drugs Inhibition of Cell Wall Synthesis
Target synthesis of b-glucans and result in an incomplete cell wall Echinocandins Binds to 1,3 b-glucan synthase Used to treat Candida and Pneumocystis Caspofungin (Cancidas™) The fungal cell wall is critical for cell viability and pathogenicity. Beyond serving as a protective shell and providing cell morphology, the fungal cell wall is a critical site for exchange and filtration of ions and proteins, as well as metabolism and catabolism of complex nutrients. Because mammalian cells lack a cell wall, it also represents an ideal and specific target for antifungal therapy. Structurally, the fungal cell wall is composed of a complex network of proteins and polycarbohydrates that varies in composition depending on the fungal species. Disruption of this protein/carbohydrate matrix results in a structurally-defective cell wall, rendering the fungal cell sensitive to osmotic lysis. Glucan synthesis inhibitors The glucan synthesis inhibitors are, collectively, agents that are presumed to block fungal cell wall synthesis by inhibiting the enzyme 1,3-beta glucan synthase. Inhibition of this enzyme results in depletion of glucan polymers in the fungal cell, resulting in an abnormally weak cell wall unable to withstand osmotic stress.

17 Disruption of Plasma Membrane
Polymyxin B Causes disruption of the plasma membrane by attaching to the phospholipids Effective against Gram negative bacteria Pseudomonas Toxic to human kidneys Topical Combined with bacitracin and neomycin in over-the-counter preparation Certain antibiotics bring about changes in the permeability of the plasma membrane of bacteria Polymyxin is produced by bacillus polymyxa Is effective against gram negative bacteria especially Pseudomonas but is also toxic to human kidneys and thus reserved for topical use.

18 Fungal Plasma Membrane
Knowledge of fungal cell structure and function is essential for understanding the pharmacology of antifungal agents. Like mammalian cells, fungi are eukaryotes with DNA organized into chromosomes within the cell nucleus and have distinct cytoplasmic organelles including endoplasmic reticulum, Golgi apparatus, mitochondria, and storage vacuoles. This homology to mammalian cells also extends to biosynthetic pathways, where fungi share similar mechanisms for DNA replication and protein synthesis. Fungi and mammalian cells both contain a cell membrane that serves and important role in cell structure, division, and metabolism. Complex lipid particles, called sterols, account for approximately 25% of the weight of the cell membrane. However, the sterol content between mammalian cells and fungal cells is different. Whereas mammalian cell membranes contain primarily cholesterol, ergosterol is the predominant sterol in many pathogenic fungi. This difference in sterol content has been exploited as the target of antifungal drug action by several classes of antifungal agents currently used to treat superficial and invasive fungal infections including the polyenes, azoles, and allylamines.

19 Antifungal Disruption of Plasma Membranes
Amphotericin B Attaches to ergosterol and disrupts membrane and causes lysis Polyene antifungals such as amphotericin B act by binding to ergosterol in the fungal cell membrane and create a pores that increase permeability eventually leading to cell death. Amphotericin B may also induce oxidative damage in fungal cells and has been reported to stimulate of host immune cells.

20 Azoles Miconazole/clotrimazole
Inhibits lanosterol a-demethylase Enzyme converts lanosterol to ergosterol Disrupts plasma membrane Miconazole/clotrimazole Triazoles (fluconazole and itraconazole) Eukaryotes such as fungi, use the same mechanisms to synthesize proteins and nucleic acids as the host the attack, therefore it is more difficult to find a point of selective toxicity in eukaryotes than in prokaryotes. Fungal infections are becoming more prevalent because of immunosuppressed individuals, especially those with AIDs Many antifungal drugs target the sterols in the plasma membrane. The principle sterol is ergosterol (in animals it is cholesterol) Azole antifungals inhibit the fungal cytochrome P A dependent enzyme 14-alpha demethylase, thereby interrupting the synthesis of ergosterol. Inhibition of this critical enzyme in the ergosterol synthesis pathway leads to the depletion of ergosterol in the cell membrane and accumulation of toxic intermediate sterols, causing increased membrane permeability and inhibition of fungal growth Azole antifungals can also inhibit many mammalian cytochrome P450-dependent enzymes involved in hormone synthesis or drug metabolism. Therefore, azole antifungals are particularly susceptible to clinically-significant drug interactions with other medications metabolized through the P450 pathway. Allylamines Allylamines work in a conceptually similar fashion to azole antifungals by inhibiting the synthesis of ergosterol. However, allylamines act at an earlier step in the ergosterol synthesis pathway by inhibiting the enzyme squalene epoxidase. Like the azoles, terbinafine has the potential for drug interactions with other medications metabolized through the mammalian cytochrome P-450 pathway. Inhibits cytochrome P450 14a-demethylase (P45014DM) Enzyme is in the sterol biosynthesis pathway that leads from lanosterol to ergosterol Miconazole/clotrimazole Triazoles (fluconzole and itraconazole Allylamines Inhibition of the fungal squalene epoxidase Results in decrease sterol synthesis, especially ergosterol Terbinafine

21 Inhibitors of Protein Synthesis
Recall prokaryotes ribosomes are structurally different from eukaryotes 70S ribosome 50S unit 30S unit Allows creation of antimicrobials that target these structures However mitochondria (eukaryotic cells) also contain 70S ribosomes similar to those of bacteria and therefore some antibiotics that target these structures and can have adverse effects on the cells of the host. Eukaryotes are 80S (consists of a 60S and 40S)

22 Inhibitors of Protein Synthesis
Chloramphenicol Broad spectrum Binds 50S subunit, inhibits peptide bond formation Serious toxicity Suppression of bone marrow Aminoglycosides Streptomycin, neomycin, gentamicin, tobramycin Bind to 30S and cause misreading of mRNA Toxicity can cause hearing impairment and/or kidney damage Reacting with the 50S portion of the 70S prokaryote ribosomes chloramphenicol inhibits the formation of peptide bonds in the growing polypeptide chain. Is a broad spectrum antibiotic from Steptomyces but is cheaper to synthesize chemically. Though it is cheap and broad spectrum it causes serious toxicity to the host, suppression of bone marrow, suppresses blood cell formation … aplastic anemia. Used is reserved as a last resort. Aminoglycosides have significant activity against gram negative bacteria

23 Inhibitors of Protein Synthesis
Tetracyclines Broad spectrum Effective against Gram + and Gram –, rickettsias, and chlamydia Interferes with tRNA attachment Forms complexes with calcium and can stain developing teeth and affect strength of developing bones. Macrolides Gram-positives Binds 50S, prevents translation Erythromycin Azithromycin Clarithromycin Discovered in the 1940s, the original TCN was produced by Steptomyces, but newer ones are semi-synthetic. Tetracycline, doxycycline, minocycline Macrolides: (can’t penetrate wall of gram negatives) erythromycin , azithromycin (Z pac) clarithromycin (Biaxin) penetrate tissues better therefore better coverage

24 Inhibition of Protein Synthesis
Antisense nucleic acids Fomiversen Cytomegalovirus and eye infections Prevents formation of 70S initiation complex Oxazolidinones (Zyvox™) Vancomycin and methicillin-resistant Staphylococcus aureus Fomivirsen (brand name Vitravene) is an antiviral drug. It is used in the treatment of cytomegalovirus retinitis (CMV) in immunocompromised patients, including those with AIDS. It is an oligonucleotide that blocks translation of viral mRNA by binding to a coding segment of a key CMV gene. It was the first antisense antiviral approved by the FDA.[1] It is 21 nucleotides in length and has the sequence: 5'-GCG TTT GCT CTT CTT CTT GCG-3' Oxazolidinones marketed in US as Zyvox. It works different than other protein synthesis inhibitors because it blocks the ability of the two ribosome subunits 50S and 30S thus no 70S complex can form and no initiation of protein synthesis can occur. Hopeful for antibiotic resistant bacteria but MRSA bacteria have become resistant to this antibiotic as well.

25 Inhibition of Metabolic Pathways
Competitive Inhibitors Sulfonamides (Sulfa drugs) Structural similar to PABA Inhibit folic acid synthesis Broad spectrum Sulfanamides were among the first synthetic antimicrobial drugs used to treat microbial disease

26 [INSERT FIGURE 10.6] Sulfanilamides are structurally similar to PABA. PABA is critical for synthesis of nucelotides needed to make DNA and RNA. Many organisms enzymatically convert PABA into dihydrofolic acid and DHF is converted to tetrahydrofolic acid (THF) a form of folic acid that is then used as a coenzyme in the synthesis of purines and pyrimidines. Sulfanilamides are structurally similar to PABA (an analog) and thus blockes the active site and thus no DHF, no THF and nucelotides. Humans do not synthesize THF from PABA instead we use folic acid found in our diet and convert them to THF thus our synthesis of nucleotides is not affected by sulfa drugs.

27 TMP is not a sulfa drug but is added to SMZ…Double whammy!!!
Trimethorim also interferes with nucleic acid synthesis. Binds to the enzyme that converts DHF to THF

28 Inhibition of Nucleic Acid Synthesis
Compounds can interfere with function of nucleic acids (nucleoside analogs) Nucleoside Analogs can distort shapes of nucleic acid molecules and prevent further replication, transcription, or translation Most often used against viruses; viral DNA polymerases more likely to incorporate and viral nucleic acid synthesis more rapid than that in host cells Also effective against rapidly dividing cancer cells

29 Zovirax™ [INSERT FIGURE 10.7]

30 Inhibitors of Nucleic Acid Synthesis
Rifampin Binds to bacterial RNA polymerase Antituberculosis Quinolones and fluoroquinolones Inhibits DNA gyrase Broader spectrum synthetic versions Ciprofloxacin: anthrax Limited use in children A number of antibiotics interfere with the processes of DNA replication and transcription in microorganisms. Some drugs with this mode of action have an extremely limited usefulness because they interfere with mammalian DNA and RNA as well. Quinilones and fluoroquinolones originated from naldixic acid (1960s) had limited activity for UTI but lead to the development of better and broader spectrum antibiotics. Inhibit DNA gyrase an enzyme necessary for correct coiling and uncoiling of repilcation of bacterial DNA Rifampin binds more readily to bacterial RNA polymerase that prevents the formation of mRNA

31 Antifungal Drugs Inhibition of Microtubules (Mitosis)
Griseofulvin Produced by a species of Penicillium Used for superficial mycoses of hair and nail (tinea capitis or ringworm) Binds selectively to keratin Blocks microtubules and inhibits mitosis Tolnaftate Mechanism of action: not known Used for athlete's foot

32 Anti-viral Medications
No peptidoglycan wall No ribosomes No plasma membrane Current anti-viral medications attack steps in viral replication Only attack actively replicating viruses Most are fake viral nucleotides, derail viral replication

33 Antiviral Drugs Nucleoside and Nucleotide Analogs
Acyclovir is best known for treating genital herpes but it is effective against most herpesvirus infection It resembles nuceloside 2’deoxyguanosine. The viral enzyme thymidine kinase combines phosphate with such nucelosides to form a nucleotide which are then incorporated into DNA Acyclovir resembles the nucleoside but cannot be incorporated into DNA

34 Antiviral Drugs Enzyme Inhibitors
Protease inhibitors Indinavir: Prevents HIV protease to trim viral proteins down to working size Prevents capsid formation Inhibit attachment Zanamivir Influenza Inhibit uncoating Amantadine Interferons prevent spread of viruses to new cells Viral hepatitis Reverse transcriptase inhibitors: RNA to DNA HIV There are a number of antiviral drugs which are enzyme inhibitors Proteases are required for production of infectious viral particles drugs developed to kill viruses are targeted at various points in viral reproduction. Such as attachment to host cells, penetration or uncoating, DNA or RNA synthesis or reproduction RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase enzyme that HIV needs to reproduce.

35 Tests to guide chemotherapy

36 Disk-Diffusion Test Also known as the Kirby-Bauer test
Petri plate is “seeded” with test organism Filter paper disks are impregnated with chemotherapeutic agents are place on surface Zone of inhibition The larger the zone the more sensitive the microbe is to the drug The further the drug diffuses out into the agar the lower it concentration Compare zone diameter to standards and the organism is reported to be sensitive, intermediate, or resistant

37 E Test More advance diffusion test
Can measure minimal inhibitory concentration (MIC) Lowest antibiotic concentration that prevents visible bacterial growth

38 Broth Dilution Test Used to determine MIC
Plus minimal bactericidal concentration Wells that show no growth (higher concentration than MIC) are cultured in drug free broth No growth = bacteriocidal Growth = basteriostatic Helps to determine if a drug is bactericidal or bacterostatic

39 Minimum Bacterial Concentration (MBC) Test
[INSERT FIGURE 10.12] This is similar to MIC test except that this test determines the amount of the drug that will kill the organism rather than just inhibit its growth as the MIC test does. Take a clear MIC tube and check to see what concentration is cidal. Here 8 is bacteriostatic and 16 is cidal.

40 Clinical Considerations in Prescribing Antimicrobial Drugs
Routes of Administration Topical application of drug if infection is external Oral – simplest; lower drug concentrations; no reliance on health care provider; patients do not always follow prescribing information Intramuscular – requires needle; concentration never as high as IV administration Intravenous – requires needle or catheter; drug concentration diminishes as liver and kidneys remove drug from circulation Must know how antimicrobial agent will be distributed to infected tissues

41 Toxicity Safety and Side Effects Disruption of Normal Flora Allergies
Exact cause of many adverse reactions poorly understood Drugs may be toxic to kidneys, liver, or nerves Considerations needed when prescribing drugs to pregnant women Allergies Although allergic reactions are rare, they may be life threatening Anaphylactic shock Disruption of Normal Flora

42 Antibiotic Resistance
A variety of mutations can lead to antibiotic resistance Mechanisms of antibiotic resistance Enzymatic destruction of drug Prevention of penetration of drug Alteration of drug's target site Alter their metabolic activity Rapid ejection of the drug Mycobacterium tuberculosis produces MfpA protein, which binds to DNA gyrase preventing the binding of fluoroquinolone drugs Resistance genes are often on plasmids or transposons that can be transferred between bacteria

43 Resistance to Antimicrobial Drugs

44 Antibiotic Resistance
Misuse of antibiotics selects for resistance mutants Misuse includes: Using outdated, weakened antibiotics Using antibiotics for the common cold and other inappropriate conditions Use of antibiotics in animal feed Failure to complete the prescribed regimen Using someone else's leftover prescription

45 Retarding Resistance Patient should finish entire course of antimicrobial Limit use of antimicrobials to necessary cases Use synergistic antimicrobials Develop new variations of existing drugs Second-generation drugs Third-generation drugs Search for new antibiotics, semi-synthetics, and synthetics Bacteriocins Design drugs complementary to the shape of microbial proteins to inhibit them Antimicrobial peptides Broad spectrum antibiotics from plants and animals Squalamine (sharks) Protegrin (pigs) Magainin (frogs) Antisense agents Complementary DNA or peptide nucleic acids that binds to a pathogen's virulence gene(s) and prevents transcription

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