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Drugs, Microbes, Host – The Elements of Chemotherapy Chapter 12 1 *How you should approach this chapter… 1. Antimicrobial chemotherapy and antimicrobics What are selection criteria? How are they used? What are adverse effects? HOW DO THEY WORK (what is their mode of action)? Blocks or inhibits: 1. 2. 3. 4. 5. Cell wall synthesis cell membrane structure/function nucleic acid structure/function protein synthesis (Specific metabolic pathways) 2 …continued… 2. Antibacterial drugs: Antibiotics and Synthetics (what is the difference?) Classes/categories; know: source, mode of action, application/spectrum Antibiotics: penicillins, cephalosporins, other B-lactam Abt, aminoglycosides, tetracyclines and other Streptomyces antibiotics, Bacillus antibiotics, other new drugs Synthetics: sulfonamides, flouroquinolones, others (narrow and broad spectrum) 3 …continued 3. Other antimicrobials (time permitting…) : (antifungals, antiprotozoal, anthelminthics, antiviral). 4. Drug resistance – How? Why? Effect? 5. Side effects of drugs – toxicity, allergy, superinfection 4 5 6 Origins of antimicrobial drugs _____________ are common metabolic products of aerobic spore-forming bacteria & fungi. bacteria in genera Streptomyces & Bacillus molds in genera Penicillium & Cephalosporium By inhibiting the other microbes in the same habitat, antibiotic producers have less competition for nutrients & space. 7 8 8 Selectively toxic Drugs should kill or inhibit microbial cells without simultaneously damaging host tissues. As the characteristics of the infectious agent become more similar to the vertebrate host cell, complete selective toxicity becomes more difficult to achieve & more side effects are seen. 9 Targets of antimicrobial drugs 1. Inhibition of _____________ synthesis 2. Disruption of _____________ structure or function 3. Inhibition of _____________ synthesis, structure or function 4. Inhibition of _____________ synthesis 5. Inhibition of other metabolic pathways 10 11 11 12 12 The Spectrum of an Antimicrobic Drug Spectrum – range of activity of a drug _____________ _____________ – effective on a small range of microbes Target a specific cell component that is found only in certain microbes _____________ _____________ – greatest range of activity Target cell components common to most pathogens (ribosomes) 13 13 1. Drugs that affect the bacterial cell wall _____________(and derivatives) and cephalosporin block synthesis of peptidoglycan, causing the cell wall to lyse. Other drugs include: vancomycin, bacitracin, monobactams, fosfomycin, cycloserine, isoniazid 14 15 2.Drugs that disrupt cell membrane function A cell with a damaged membrane dies from disruption in metabolism or lysis. These drugs have specificity for a particular microbial group, based on differences in types of lipids in their cell membranes. _____________ interact with phospholipids and cause leakage, particularly in gramnegative bacteria Amphotericin B and nystatin form complexes with sterols on fungal membranes which causes leakage. 16 4. Drugs that disrupt cell membrane function 17 3. Drugs that inhibit nucleic acid synthesis may block synthesis of nucleotides, inhibit replication, or stop transcription _____________ inhibition – drug competes with normal substrate for enzyme’s active site _____________ effect – an additive effect, achieved by multiple drugs working together, requiring a lower dose of each 18 2. Drugs that inhibit nucleic acid synthesis (and also 4. drugs that block metabolism) _____________(ciprofloxacin) blocks gyrase _____________ blocks RNA pol (transcription) • Sulfonamides and _______________________________ (synergistic) -- block enzymes required for tetrahydrofolate (THFA) synthesis • THFA is needed for DNA & RNA synthesis. (coenzyme) 19 Figure 12.6 (a) 20 20 Competitive inhibition of PABA by sulfa drug 21 21 4. Drugs that block protein synthesis Ribosomes of eucaryotes differ in size and structure from procaryotes, so antimicrobics usually have a selective action against procaryotes. But they can also damage the eucaryotic _____________ . Abt can block mRNA, peptide bonds, tRNA binding, etc. 22 23 23 Survey of major antimicrobial drug groups Antibacterial drugs Antibiotics Synthetic drugs Antifungal drugs Antiparasitic drugs Antiviral drugs About 260 different antimicrobial drugs are classified in 20 drug families. 24 Antibacterial antibiotics Penicillins Cephalosporins Other beta-lactam antibiotics Aminoglycosides Tetracycline antibiotics Chloramphenicol Other Streptomyces antibiotics The Bacillus antibiotics New classes 25 Penicillins Cell wall inhibitors. Source: Penicillium Examples: “-cillin” such as penicillin, ampicillin, amoxicillin, methicillin etc. MOA: blocks PGN synthesis (CW) Application: Gram positive, some Gram neg. Structure: B-lactam, thiaxolidine, varying side chains Problems: allergy, bleeding, diarrhea (host); resistance in bacteria (via lactamase, penicillinase) 26 Penicillins 27 Cell wall inhibitors. 28 Cephalosporins Cell wall inhibitors. Source: Cephalosporium Examples: Ceph- cef- kef- drugs (ex. Cephalexin) MOA: blocks CW synthesis Application: depends on “generation” Structure: B-lactam, ring, varying side chains (2) Problems: less allergies, but some need parenteral administration, can affect WBC 4 generations exist: each group more effective against gram-negatives than the one before with improved dosing schedule and fewer side effects 29 Cephalosporins - generations Gram+ cocci, some Gram- More G- than 1st gen (Enterobacter, Proteus, Haemophilus) Broad spectrum against enteric bacteria with beta-lactamases Ex. Cephalexin (Keflex) cefepime – widest range; both gramnegative and grampositive 30 Cell wall inhibitors. Other beta-lactam antibiotics Imipenem – broad-spectrum drug for infections with aerobic and anaerobic pathogens; low dose, oral, few side effects Aztreonam –isolated from bacteria Chromobacterium violaceum – newer narrowspectrum drug for infections by gram-negative aerobic bacilli. May be used by people allergic to penicillin- it is a monobactam. Given IV. 31 Disrupt cell wall synth. MOA of B-lactam antibiotics PGN (made of NAM and NAG) are crosslinked by the enzyme transpeptidase This is the final step in CW syntheis B-lactam abt inhibit transpeptidase – they mimic the normal substrate and bind to the active site. 32 Cell wall inhibitors. Non Beta-lactam Cell Wall Inhibitors _____________–narrow-spectrum, effective against penicillin & methicillin resistant staphylococcal infections; very toxic, hard to administer, restricted use – inhibits CW synthesis (NAM/NAG polymerization) _____________ MOA: Blocks CW synthesis; produced by a strain of Bacillus subtilis; Application: narrow-spectrum, major ingredient of neosporin ointment (topical) Isoniazid –works by interfering with mycolic acid synthesis; used with rifampin to treat TB; blocks FA reductase (metabolism) (Nydrazid ®) 33 33 2. Antibiotics That Damage Bacterial Cell Membranes _____________– MOA: peptide with fatty acid component, detergent activity Application: narrow-spectrum; drug resistant Pseudomonas aeruginosa & UTI Problems: limited by toxicity to kidney; 34 34 3. Drugs that Act on DNA or RNA Fluoroquinolones – work by binding to DNA gyrase and topoisomerase IV Broad spectrum effectiveness Concerns have arisen regarding the overuse of quinoline drugs CDC is recommending careful monitoring of their use to prevent ciprofloxacin-resistant bacteria norfloxacin, _____________ – UTI, STD, GI, osteomyletitis, respiratory & soft tissue infections sparofloxacin, levofloxacin – pneumonia, bronchitis, sinusitis 35 35 3. Drugs that Act on DNA or RNA _____________– limited spectrum, cannot pass through many cell membranes, used to treat gram-positive bacteria, TB, leprosy Blocks TRANSCRIPTION 36 4. Drugs That Interfere with Protein Synthesis Aminoglycosides Products of various species of soil actinomycetes in genera Streptomyces and Micromonospora 37 37 aminoglycosides Source: Actinomycetes (like Streptomyces) Examples: streptomycin, gentamicin, amikacin, neomycin MOA: blocks translation (inhibits initation, binds 30S ribosomal subunit) Application: relatively broad (aerobic G-, TB) Structure: 6C ring with 2 amino sugars Problems: diarrhea, kidney, EAR problems Sometimes combined with Amp to treat systemic G+ infections - endocarditis 38 4. Drugs That Interfere with Protein Synthesis Aminoglycosides – Broadspectrum, inhibit protein synthesis, especially useful against aerobic gramnegative rods and certain gram-positive bacteria _____________– bubonic plague, tularemia, TB Gentamicin – less toxic, used against gram-negative rods Newer – tobramycin and amikacin gram-negative bacteria 39 39 Other antibiotics produced by Streptomyces: A. __________ MOA: block protein synthesis (30S) Application: Broad-spectrum, Doxycycline & minocycline – oral drugs taken for STDs, Rocky Mountain spotted fever, Lyme disease, typhus, acne & protozoa Problems: kills GI flora, can discolor teeth in children, causes photosensitization 40 B. _____________ Source: Streptomyces venezuelae– is totally synthetic now MOA: Blocks peptide bond formation Application: Potent broad-spectrum drug with unique. Typhoid fever, brain abscesses, rickettsial & chlamydial infections Structure: nitrobenzene Problems: **Very toxic, restricted uses, can cause irreversible damage to bone marrow 41 C. _____________ and other macrolide antibiotics MOA: Attaches to ribosome (50S) Application: Broad-spectrum, fairly low toxicity. Taken orally for Mycoplasma pneumonia, legionellosis, Chlamydia, pertussis, diphtheria and as a prophylactic prior to intestinal surgery (also strep throat, ear infection) For penicillin-resistant – gonococci, syphilis, acne Newer semi-synthetic macrolides – clarithomycin, azithromycin (Z-pak®) Structure: macrolide, large lactone ring with sugars 42 Macrolide antibiotics 43 5. Drugs That Block Metabolic Pathways Most are synthetic; most important are ____________ or sulfa drugs - first antimicrobic drugs Narrow-spectrum; block the synthesis of folic acid by bacteria (and indirectly DNA synthesis) Sulfisoxazole – shigellosis, UTI, protozoan infections Silver sulfadiazine – burns, eye infections _____________ – given in combination with sulfamethoxazole – UTI, PCP Sulfonamides and trimethoprim block THFA synthesis 44 44 Structure of sulfonamides 45 45 New classes of antibiotics Formulated from pre-existing drug classes Three new drug types: 1. Fosfomycin trimethamine – a phosphoric acid; effective as alternate treatment for UTIs, inhibits cell wall synthesis 2. _____________– effective against Staphylococcus & Enterococcus that cause endocarditis & surgical infections; inhibits protein synthesis (binds 50S) 3. Daptomycin – directed mainly against gram-positive; disrupts membrane function 46 Newly Developed Classes of Antimicrobials Ketolides – telitromycin (Ketek), new drug with different ring structure from Erythromycin; used for infection when resistant to macrolides _____________– linezolid (Zyvox®); synthetic antimicrobial that blocks the interaction of mRNA and ribosome Used to treat _______________________ _______________________________________ _________________________________________ 47 47 Antifungal agents Problem: _________________________ ___________________________________ drug groups: Macrolide polyene antibiotics Griseofulvin Synthetic azoles flucytosine 48 Macrolide polyene MOA: bind fungal membranes, increase permeability (fungal membranes have sterols) Examples: Amphotericin B – mimic lipids, most versatile & effective, topical & systemic treatments Nystatin – topical treatment Structure: steroid Applications: Candida, ringworm, histoplasmosis, cryptococcus 49 Other antifungals Griseofulvin Application: stubborn cases of dermatophyte infections, nephrotoxic Synthetic azoles – Application: broad-spectrum; Examples: ketoconazole, clotrimazole, miconazole; Structure: complex ring structure Flucytosine – MOA/Structure: analog of cytosine; Application: cutaneous mycoses or in combination with amphotericin B for systemic mycoses 50 Antifungal drugs Azoles Flucocytozine 51 Antiparasitic Chemotherapy 1. Antiprotozoan drugs Antimalarial drugs – quinine, chloroquinine, primaquine, mefloquine – used as prophyllaxis or treatment Anti -amoeba, -flagellates, -ciliates– Used for infections with Entamoeba, Giardia, Trichomonas metronidazole (Flagyl), quinicrine, sulfonamides, tetracyclines 52 52 Antiparasitic chemotherapy 2. Antihelminthic drugs – immobilize, disintegrate, or inhibit metabolism Niclosamide – destroys scolex Praziquantel – tapeworms, trematodes Mebendazole, thiabendazole – broad-spectrum – inhibit function of microtubules, interferes with glucose utilization and disables them Pyrantel, piperazine – paralyze muscles Ivermectin – works on neurotransmitters and paralyzes worm or insect 53 Antiviral drugs – 3 MOA Block _____________ into host cell Fuzeon – blocks HIV by preventing interaction of receptors Amantidine – blocks influenza entry and release (blocks fusion and uncoating) Tamiflu - blocks influenza neuraminidase (needed for entry) Block _______________________________ Acyclovir – herpesviruses – binds viral DNApol (Zovirax) Purine analog. Also Valacyclovir (Valtrex) AZT (zidovudine) – thymine analog – HIV – RT inhibitor so viral genome can’t be replicated Nevirapine - blocks enzyme - RT binding site no RNA DNA Prevent ___________ of viral particles and release Protease inhibitors (Saquinavir, Ritonavir)– HIV – inactivate enzyme so viral proteins are not functional 54 55 55 Interferon IFN is a human cytokine, naturally produced by cells (leukocytes) as part of the immune response It is the ___________________________ in your body! (also anticancer) recIFN can be used therapeutically: Shorten herpes healing time Reducing colds and warts Slowing cancer progress; treating rare cancers Treating HepC, papillomavirus, Kaposi’s sarcoma 56 Four Mechanisms drug resistance 1. Drug _______________ – penicillinases 2. Decreased _______________ to drug or increased elimination of drug from cell 3. Change in _______________ patterns 4. Change in drug ________________ Drug resistance can be carried as R factors (plasmids carrying resistance genes) 57 58 Mechanisms drug resistance 59 Selection for drug resistance Go to this link: http://www.sumanasinc.com/scienceinfocus/antibiotics/antibiotics_fla.html 60 Human behavior that leads to drug resistance Doctors over-prescribing antibiotics asking for antibiotics when they are not needed (viral infections) failing to finish an antibiotic prescription saving the unused medication and taking it later for another illness taking antibiotics before symptoms arise simply to avoid getting sick 61 Other factors that lead to microbial drug resistance Hospital setting – Lots of Abt being used, weakened (sick and easy to infect) hosts Resistance in ______________ on antibiotic regimens (these microbes are also in the meats we eat) Resistance spreads rapidly both geographically (exporting foods) and within populations (transformation, conjugation, etc.) Viruses – have rapid ___________ rate (HIV) 62 63 63 Side effects of drugs 1. Toxicity to organs – liver (detox), kidney (excretion; sulfonamides), GI (kills flora), bone marrow (anemia, chloramphenicol), nervous system (aminoglycosides), Teeth/bones (tetracycline) 64 2. Allergic responses – true penicillin allergy is to benzlpenicilloyl (product of metabolism of Pen) 3. Suppression and alteration of microflora 65 66 66