Exam 3: Ch 10 Flashcards by Lyssa Rose

Use of chemical compounds to treat infectious (microbial) and non- infectious (e.g. cancer) diseases.

Chemotherapy

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An ideal in chemotherapy that an antimicrobial agent kills the offending microbe but doesn’t harm host. Historically, reminiscent of the “magic bullet” of Paul Ehrlich, who did what?

Selective toxicity

He used arsenical compound called “Salvarsan” to treat syphilitic patients.

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Structural and physiological differences from eukaryotic cells allow many therapeutic approaches and options with treating these

Prokaryotic cells

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These in the membranes of the gram-negative cells allow only small and hydrophilic molecules.

Porins

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These types of cells are susceptible to penicillin

Gram-positives

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These pathogens are much more difficult because these cells are similar to the host’s.

Eukaryotic cells

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These pathogens are difficult to deal with because these are intracellular and control the host’s genetic functions

Viral pathogens

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Inhibits growth and reproduction of the microbe. It’s best administered in immunocompetent individuals; allows for immune system to work against microbes. Less costly and fewer side effects.

Bacteriostatic

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Lethal to microbes that are advisable for immunocompromised individuals (e.g. oncology and AIDS patients)

Bactericidal

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Effective against gram-positive and gram-negative bacteria. Used if bacterium causing infection is unknown (Emperical therapy or “Shotgun Approach”)

Broad spectrum antibiotics

Disadvantage normal microbiota are also destroyed encouraging growth of opportunists.

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Potential pathogens that are part of the normal microbiota of humans that can survive antimicrobials. When the med reduces microbial antagonism, superinfections occur.

Opportunists

Candida albicans

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Drugs that work only against a few kinds of pathogens (maybe positive mostly?)

Narrow spectrum

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Proposed the term chemotherapy. Magic bullets. Resulted in the arsenic compound that killed tryapnosome parasites and another that worked against the agent of syphilis.

Paul Ehrlrich

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Reported the antibacterial action of penicillin released from Penicillium notatum. 1928.

Alexander Fleming

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Extracted and mass produced penicillin from Penicillium chryseogenum. 1940.

Howard Florey and Ernst Chain

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Discovered sulfanilamide, which was the first practical antimicrobial agent good for treating a wide array of bacterial infections.

Gerhard Domagk

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Discovered other organisms are a useful source for antimicrobials, most notably Streptomycin derived from Streptomyces bacteria.

Selman Waksman

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Inhibition of cell wall synthesis

Penicillins and Cephalosporins

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Inhibition of protein synthesis

Aminoglycosides and Tetracycline

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Inhibition of plasma membrane

Polymyxin and Amphotericin B

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Inhibition of nucleic acid synthesis

Cirpofloxacin and Nalidixic acid

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Inhibition of folic acid synthesis

Trimethoprim-sulfamethoxazole

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Bactericidal – cell lysis occurs as water moves into the cell. Bind and block peptidases involved in peptide cross bridges linking the NAM subunits. Both contain beta-lactam ring hence called beta-lactam antibiotics.

Penicillins and Cephalosporins

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Molecular structure of penicillins?

Thiazolidine ring
Beta-lactam ring
Variable side chain (R group)

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Penicillin that requires injection, destroyed by stomach acid, does not stay long enough in the blood circulation to be effective at 2 hours

Natural Penicillin G

Oral penicillin, stays longer in the blood at 24 hours

Natural Penicillin V

Extracted entirely from mold. Effective agianst gram+ bacteria and spirochetes.

Natural Penicillins Susceptible to the action of penicillinase - penicillin hydrolyzed into penicilloic acid (no antimicrobial activity), beta lactam ring broken by enzyme

Partially synthesized penicillin that retains the core penicillin moelcule.

Oxacillin (or Methicillin): resistant to penicillinase | Ampicillin: extended spectrum penicillin

Good against penicillinase producing bacteria. Includes clavulanic acid and sulbactam.

Penicillins used with beta-lactamase inhibitors

Amoxacillin + clavulanic acid. Preferred antibiotic for pediatric patients

Augmentin Penicillin + beta-lactamase inhibitor

Ticarcillin + clavulanic; same as Augmentin.

Timentin Penicillin + beta lactamase inhibitor

Broad spectrum penicillins that are highly resistant to beta-lactamases. Which is good against Pseudomonas aeruginosa?

Carbapenems | Imipenem

Penicillins where the beta-lactam ring is alone and not fused with another ring. Which is especially useful in treating P. aeruginosa infections?

Monobactams | Aztreonam

Derived from Cephalosporium acremonium. Beta lactam antibiotic like penicillin. Main ring different from penicillin, 2 sites for R groups.

Cepahlosporins Broad-spectrum or extended spectrum antibiotic; 2nd, 3rd, 4th, 5th generations more effective against Gram-negatives. (e.g. Keflex, Cefoxitin)

Produced by the bacterium Bacillus subtilis.Blocks transport of NAG and NAM from cytoplasm out to the wall preventing cell wall formation. Very toxic; applied only topically. Effective against gram+ cocci

Bacitracin Polypeptide antibiotic

A glycopeptide that hinders peptidoglycan elongation by interfering with alaline-alanine bridges that link NAM subunits in gram+. “Antibiotic of last resort”, has been used for MRSA.

Vancomycin Polypeptide antibiotic Relatively toxic and costly

Explain Vancomycin resistance and its effects?

Strains of S. aureus have developed that are resistant to Vancomycin (VRSA and VRE) and because of this medical emergency, the antibiotic Synercid was rushed through FDA approval. Emergence of Synercid resistance resulted in the release of Linezolid.

Inhibits the synthesis of mycolic acids and is used in combination with other drugs to treat TB (takes months to administer) Oral antibiotic.

Isoniazid hydrazide (INH)

Inhibits incorporation of mycolic acid into cell wall; also an anti-TB drug.

Ethambutol

Use of drugs of different modes of action (e.g. INH+ Streptomycin + Pyrazinamide + Cycloserine) – due to emergence of resistance of bacterium

Combined therapy TB requires it

Alters shape of 30s ribosomal subunit. First group of antibiotics with significant activity against gram- infections because it's broad spectrum Not being used so much; can cause permanent damage to the auditory nerve (tinnitus) and toxic to kidneys

Aminoglycosides Monitor aminoglycoside levels of patients (e.g. Pre-and Post-Gentamicin levels for kidneysand stuff) Streptomycin for TB Neomycin used topically

Interferes with tRNA attachment. Broad spectrum, therefore, superinfections often happen. Penetrates tissues well and valuable against Chlamydia infections. What are the side effects?

Tetracycline | Discoloration of teeth in children, live damage, use contraindicated for pregnant women.

Binds with 50s ribosomal subunit and inhibits peptide bond formation. Broad-spectrum – useful in treating Salmonella infections (e.g. typhoid fever). Cheap synthetic antimicrobial. Side effects?

Chloramphenicol | Supressed bone marrow-aplastic anemia

Binds with 50s ribosomal subunit and prevents ribosomal translocation. A macrolide. Bactericidal. Used to treat penicillin resistant strains. Only effective against gram+ bacteria. Side effects?

Erythromycin | GI disturbance

Large molecule containing lactone ring. Azithromycin (Zithromax) and Clarithromycin

Macrolide

Binds with 50s ribosomal subunit and inhibits translation | This example drug (dalfopristin + quinopristin) is used for Vancomycin-resistant bacteria, synergistic effect.

Streptogramins | Synercid

Binds with 50s ribosomal subunit and prevents formation of 70S ribosome. Bactericidal; affect gram+ ; e.g. Linezolid

Oxazolidinones

Interact with membrane phospholipids. Topical -combined with Bacitracin and Neomycin as over-the counter antibiotic

Polymyxins | Cause cell membrane damage

Anti-fungal agent. Forms complexes with sterols in the membrane, causing cytoplasmic leakage. Side effect?

Amphotericin B Renal toxicity, cell membrane nehprotoxicity

Inhibits mRNA synthesis. Used for the treatment of TB along with INH, etc.

Rifampin (Rifamycin)

Inhibit DNA synthesis by the DNA gyrases). This example oral antibiotic is useful for UTIs, prophylaxis and treatment of Anthrax. It crosses blood brain barrier

Quinolones and Fluoroquinolones Ciprofloxacin

Synthetic drug derived from dyes (Prontosil of Domagk). Treatment of UTIs using Bactrim or Septra. Pneumocystis pneumonia in AIDS patients. Analogs of folic acid. Competitive enzyme inhibition - prevents the metabolism of DNA, RNA, and amino acid.

Sulfonamides | Synergistic combination as Trimethoprim /Sulfamethoxazole.

Interfere with sterol synthesis, injuring cell membrane. Topical and systemic use; cutaneous mycoses such as athlete’s foot and yeast infections and systemic mycoses. (e.g. Miconazole, Itraconazole)

Azoles

Pyrimidine analogue and thymidylate synthase inhibitor. Fungistatic at best. Used in cases of Amphotericin B resistance.

5-flurocytosine

Blocks microtubule assembly and interferes with cell division. Used for skin infections

Griseofulvin

Inhibit the spread of viruses to new cells.

Interferons

Act through competitive inhibition of HIV's ___ enzymes and virus cannot be assembled.

Protease inhibitor

Inhibition of DNA/RNA synthesis. Nucleoside and non-nucleoside analogs. One is used for Herpes virus infections. Then drugs used for HIV.

Acyclovir | Azidothymidine - AZT

Antiprotozoal drugs. Derivatives used for malaria. Another acts on parasitic protozoa and obligate anaerobic bacteria.

Quinine | Metronidazole (Flagyl)

For bacteriostatic agents. Minimum concentration of the antibiotic that inhibits growth of test bacterium. Tube dilution method or newer automated methods using microtiter plates (e.g. Vitek). Computer interfaced. E-Test – combines disc diffusion principle and MIC determination.

Minimum inhibitory concentration test

Test for bactericidal agents

Minimum bactericidal concentration test (MBC)

Routes of administration?

Topical application for external infections. Oral route requires no needles and is self-administered. Intramuscular administration delivers drug via needle into muscle. Intravenous administration delivers drug directly to bloodstream. Must know how antimicrobial agent will be distributed to infected tissues

Possibilities of drug-host interactions?

Toxicity to organs – liver, kidney, nerves. Allergic reactions are rare but maybe life-threatening. Suppression or alteration of normal microbiota may result in secondary or superinfections

Antimicrobial resistance mechanism like penicillinase action on the peptidoglycan layer.

Enzymatic destruction of the drug

Antimicrobial resistance mechanism wherein porin channels of gram- bacteria prevent the entry of large molecules

Prevention of penetration of the drug

Antimicrobial resistance mechanism. Structural or biochemical – e.g. mecA gene product PBP2 results in methicillin resistance in S. aureus.

Alteration of drug's target site

Antimicrobial resistance mechanism. Efflux pumps of P. aeruginosa

Rapid ejection of the drug

Other antimicrobial resistance mechanisms

Natural Selection | Biofilm retards antibiotic, antibody, and phagocyte activities.

Resistance gens are often on what that can be transferred between bacteria?

Plasmids or Transposons

Abuse and misuse of antibiotics

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

Ribosomal subunits of different kinds of cells?

Prokaryotes: 70S with 50S and 30S subunits Eukaryotes: 80S with 60S and 40S subunits