Microbiology Road Map I-1

Microbiology Road Map I Roadmap Objectives 1. Know why an antimicrobial drug must have selective toxicity? antimicrobial therapy is to kill or inhibit the infecting organism without damaging the host 2. Know the difference between a broad-spectrum and narrow-spectrum antimicrobial agent and under what conditions might each be used? Narrow-spectrum antibiotics target a few types of bacteria, broad-spectrum antibiotics when they're not needed can create antibiotic-resistant bacteria that are hard to treat. 3. What are the general modes of actions used by therapeutic antimicrobials to target infectious agents? interfering with cell wall synthesis, plasma membrane integrity, nucleic acid synthesis, ribosomal function, and folate synthesis . 4. What are the common side effects potentially observed with the use of therapeutic antimicrobials? Nausea, indigestion, vomiting, diarrhea, bloating or feeling full, stomach pain 5. How can genetic resistance to antimicrobials arise in bacterial cells? Through mutation and selection 6. What are the mechanisms of antimicrobial resistance that have been identified? Enzyme inactivation and modification 7. How can drug resistance be limited? Prevent infections by ensuring your hands, instruments, and environment are clean 8. How can the sensitivities of microbes to therapeutic antimicrobial agents be determined? By using broth and agar dilution methods 9. What are the characteristics of an ideal therapeutic antimicrobial agent? agent that kills or inhibits the growth of all harmful bacteria in a host 10. What are examples of antibacterial, antifungal, antiviral, antiprotozoal, and antihelminthic therapeutic antimicrobials? Road Stop (Antimicrobial Chemotherapy) Define the following terms: chemotherapy: _____ a drug treatment that uses powerful chemicals to kill fast-growing cells in your body _________________________________________________________________________ chemotherapeutic agents (drugs): ______ medicine you receive to kill cancer cells _________________________________________________________

antimicrobial agents: _______ a natural or synthetic substance that kills or inhibits the growth of microorganisms such as bacteria, fungi and algae __________________________________________________________________ antibiotic: _ medicines that fight bacterial infections in people and animals _________________________________________________________________________________ synthetic (antimicrobial) drugs: ___ ulphonamides, cotrimoxazole, quinolones, anti-virals, anti-fungals, anti-cancer drugs, anti-malarials, anti-tuberculosis drugs, anti-leprotics, and anti- protozoals______________________________________________________________ semisynthetic (antimicrobial) drugs: ______ derivatives of natural antibiotics with slightly different but advantageous characteristics_______________________________________________________ Road Stop (Kinds of side effects) Describe each of the following potential side effects to therapeutic antimicrobials. (1) Toxicity gastrointestinal effects (eg, nausea, vomiting, diarrhea, abdominal pain, loss of appetite, bloating), often owing to disturbance of gut flora. Broad-spectrum antibiotics are also likely to cause secondary Candida species overgrowth, especially in those with diabetes. (2) Allergy The use of antimicrobial agents has been associated with an increased incidence of allergic diseases, including asthma, atopic dermatitis, and less commonly, anaphylaxis. (3) Disruption of normal flora Disruption of normal enteric flora may be caused by use of antimicrobials, stress, or prolonged diarrhea. a. What is a superinfection? Superinfection is a disease caused by an organism that is often an opportunist or one that was present in low numbers. Superinfection is a sequel to removal of the normal flora by antibiotic treatment. Road Stop (Antimicrobial resistance) A resistant microorganism is one that was once susceptible to an antimicrobial agent, but is no longer affected by it. (1) What are two ways in which genetic resistance to antimicrobials are acquired? mutation and selection, bacteria can develop defense mechanisms against antibiotics a. Compare the two types of acquired genetic resistance. Which one is more likely to encode resistance to multiple antibiotics?

Carbapenems Gram-negative bacteria mechanism-based inhibitors of the peptidase domain of PBPs Bacitracin inhibits bacterial cell- wall biosynthesis by targeting extracellular, membrane- associated pyrophosphate groups inhibit bacterial synthesis of tetrahydrofolic acid Vancomycin d-Ala-d-Ala terminus of peptidoglycan (PG) ability to inhibit bacterial cell wall biosynthesis Polymyxins gram-negative bacterial infections disrupting the membrane integrity leading to the permeabilization of the bacterial cell. Aminoglycosides bacterial ribosome, inhibit protein synthesis by binding, with high affinity, to the A-site on the 16S ribosomal RNA of the 30S ribosome Tetracyclines 30S ribosomal subunit, inhibit the 30S ribosomal subunit, hindering the binding of the aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex Chloramphenicol 50 S subunit of the 70 S ribosome The antiemetic effect of chlorpromazine stems from the combined blockade of histamine H1, dopamine D2, and muscarinic M1 receptors in the vomiting center Macrolides bacterial ribosome their ability to bind the bacterial 50S ribosomal subunit causing the cessation of bacterial protein synthesis Lincosamides Gram-positive pathogens an reversible binding to the 50S ribosomal subunit and resultant suppression of protein synthesis. Rifampin the pocket of the RNA polymerase β subunit within the DNA/RNA channel, but away from the active site inhibit bacterial DNA-dependent RNA polymerase, Quinolones the essential blocking DNA replication and

bacterial enzymes DNA gyrase and topoisomerase IV inhibiting synthesis and cell division Sulfonamides folic acid biochemical pathway of bacteria. competitive antagonists and structural analogues of p- aminobenzoic acid (PABA) in the synthesis of folic acid Isoniazid a long-chain enoyl-acyl carrier protein reductase (InhA), a inhibit bacterial cell wall synthesis following activation by the bacterial catalase–peroxidase enzyme KatG in Mycobacterium tuberculosis Ethambutol Nitrofurans microbial enzyme systems, including those involved in carbohydrate metabolism. activated inside bacteria by reduction via the flavoprotein nitrofurantoin reductase to unstable metabolites, which disrupt ribosomal RNA, DNA and other intracellular components. Antifungal drugs Imidazoles & Triazoles imidazole derivatives as anti-AD with multiple targets reviewed from the data available on Pubmed. inhibiting cytochrome P450- dependent enzyme, the lanosterol 14-α-demethylase Polyenes fungi bind to ergosterol in the cell membrane of fungi and form aqueous pores that promote leakage of intracellular ions and disrupt active transport mechanisms dependent on membrane potential. Amphotericin B Ergosterol, the principal sterol in the fungal cytoplasmic membrane, binds to ergosterol in the fungal cell membrane, which leads to the formation of pores, ion leakage and ultimately fungal cell death. Nystatin antifungal binding to sterols in the plasma membranes of fungi causing the cells to leak, eventually leading to fungal cell death Griseofulvin antifungal enters the dermatophyte through

tubulin and thereby blocking polymerization of tubulin dimers in the intestinal cells of parasites. Piperazine acts as a γ-aminobutyric acid (GABA) agonist, causing chloride channel opening, neural hyperpolarization and flaccid paralysis of susceptible parasites. Reaching Your Destination: Compass Checklist Questions After reading chapter 10 and 11, you should be able to answer the following checklist questions. (1) What does it mean for an antibiotic to have selective toxicity? the ability to damage the infecting organism without damaging the host. (2) What is the difference between a broad-spectrum antibiotic and a narrow-spectrum antibiotic? Narrow-spectrum antibiotics are effective against a certain group of bacterial types while broad- spectrum antibiotics are effective against a broader number of bacterial types and, thus, can be used to treat several infectious diseases (3) What are the potential modes of action of therapeutic antimicrobial agents? Various antimicrobial agents act by interfering with cell wall synthesis, plasma membrane integrity, nucleic acid synthesis, ribosomal function, and folate synthesis (4) What are the potential side effects of antimicrobial agents? Common side effects of antibiotics can include rash, dizziness, nausea, diarrhea, or yeast infections (5) How are the genes responsible for antimicrobial resistance acquired by microbes? horizontal gene transfer (6) What mechanisms are used by microbes to mediate resistance to antimicrobials? enzymatic degradation of antibacterial drugs, alteration of bacterial proteins that are antimicrobial targets, and changes in membrane permeability to antibiotics. (7) How can the development of drug resistance be slowed? Only use antibiotics when prescribed by a certified health professional. (8) What are the attributes of an ideal therapeutic antimicrobial agent and how are they similar or different from the attributes of an ideal chemical disinfectant? Broad spectrum: should have a wide antimicrobial spectrum; Fast acting: should produce a rapid (9) What are some of the key antibacterial, antifungal, antiviral, antiprotozoal, and antihelminthic drugs that are used to fight infection? (10) Herpes Simplex Virus 1 & 2 (HSV-1 / HSV-2) . Chickenpox, Shingles . Epstein-Barr Cytomegalovirus (CMV) . Kaposi's Sarcoma Off the Map Resistance to antimicrobial chemotherapeutic agents

The resistance of microorganisms to therapeutic antimicrobial agents is a serious and growing threat to public health. In this chapter you have seen how resistance can arise within a microbial population and read about the mechanisms of antimicrobial resistance. To better understand how rapidly antimicrobial resistance can spread within a population of microorganisms and how this can affect the clinical treatment of disease, click on the following link from the CDC’s Morbidity and Mortality Weekly Report : http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5614a3.htm (1) This article concerns drug resistance in Neisseria gonorrhoeae . What disease(s) or condition(s) are caused by this organism? How many cases were reported in the United States in 2005? In addition to reading the text, see the Box at the bottom of the article. (2) What is the current recommendation for the treatment of gonorrhea? How did the recommendation change in 2006? (3) What do fluoroquinolones target? What is the mechanism of resistance to fluoroquinolones? Are these mutations chromosomal or plasmid-borne? See http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3028768/ for this information . (4) Where did fluoroquinolone-resistant Neisseria gonorrhoeae first arise? (5) Describe the course of use of fluoroquinolones to treat gonorrhea from 1993 to 2006. In other words, starting in 1993, indicate where and when fluoroquinolone resistance reached high enough incidence to warrant removing that drug as a recommended treatment. (6) The CDC has recommended discontinuing the use of fluoroquinolones for the treatment of gonorrhea due to the high incidence of resistant strains. Are all N. gonorrhoeae resistant to fluoroquinolones now? What is the average incidence of resistance required in the United States for a drug to be considered effective for use? See Editor’s note for this information . (7) Click on the link to the article’s table or scroll to the table at the bottom of the article. Find three cities nearest to your location. What is the average incidence of resistant N. gonorrhoeae in those locations in 2006? How did that change from 2004 to 2006? (8) As stated in the Editor’s note, ‘the CDC strongly recommends that all state and local health department laboratories maintain or develop the capacity to perform culture [of N. gonorrhoeae ].’ Why is this?