Microbiology Ch 19

Clavulanic acid is an A. Penicillin-binding protein modifier B. β-lactamase inhibitor C. Efflux pump inhibitor D. Immune response stimulator

B. β-lactamase inhibitor

The most appealing target for antibiotics is the bacterial cell wall, because it is on the outside of the cell.

False

Bacteria that have evolved the ability to produce β-lactamase have become resistant to penicillin because all forms of penicillin contain this ring structure.

True

People began to think that infectious disease was a thing of the past because of antibiotics.

True

The efficacy of penicillin is highest during the _____ phase of the bacterial life cycle. A. Static B. Active growth C. Stationary D. Death

B. Active growth

Explain why are antibiotics that are protein synthesis inhibitors are excellent choices for therapy in the context of toxicity? Why might large doses of protein synthesis inhibitor antibiotics show toxic effects in eukaryotic cells even though they meet the criterion for selective toxicity?

Bacteria possess ribosomes that are constructed of different proteins and rRNA molecules from those in eukaryotic ribosomes. Antibiotics that target prokaryotic ribosomes are selectively toxic as they will have no effect on eukaryotic ribosomes and will not be toxic to the patient if used within the appropriate therapeutic dose range. Although they are selectively toxic, large doses of a protein synthesis inhibitor may have adverse effects on the patient as it may affect the mitochondria, which contain the same ribosomes as prokaryotic cells.

Why is it advantageous for bacteria such as Streptomyces species to synthesize antibiotics? Explain three ways in which antibiotic-producing microorganisms protect themselves from the effects of these compounds.

Bacteria such as Strepomyces produce antibiotics as a strategy to maximize their access to limited nutrients and oxygen by inhibiting the growth of nearby competing bacteria. The ways bacteria can protect themselves from the damaging effects of their own antimicrobials include: first, synchronizing antibiotic synthesis with the stationary phase of growth, where antibiotics have the least effect as the bacteria are not actively dividing; second, maintaining low intracellular antibiotic concentrations by the production of inactive forms of antibiotic that are then activated by extracellular enzymes; and third, by modifying potential self-targets, such as their cell wall or polymerase molecules, so that they are no longer a target for the antibiotics produced.

Ampicillin is referred to as a semi-synthetic form of penicillin because it blocks the synthesis of half the cell wall components.

False

The treatment of malaria has changed since quinine was first used in the 1600s. What has changed and why?

Quinine has been modified into several synthetic forms, including chloroquine and mefloquine, and these drugs all act against the asexual stage of Plasmodium when resident in red blood cells. Resistance has developed against chloroquine and there are now widespread chloroquine-resistant strains in many areas of the world. In these areas other drugs such as mefloquine are substituted, although chloroquine is still in heavy use in sub-Saharan Africa. An alternative to quinine-based drugs, is artemisinin, and this is now widely prescribed for malarial infection. Although it is recommended for use in combination with other drugs, such as chloroquine or mefloquine, to reduce the chance of resistance developing, artemisinin resistance has been reported in Southeast Asia and Thailand. Other drugs include primaquine, which targets the liver stage of the parasite and is used to treat relapsing forms of malaria, and halofantrine, which is effective against all Plasmodium species, even multi-drug resistant P. falciparum, but can cause major cardiac side effects. As with antibiotics, the development of resistance to antimarial drugs is an ongoing problem.

Discuss selective toxicity as it relates to antimicrobials.

Selective toxicity is the ability to cause destruction of the disease-causing organism but with little or no effect on the human host. This requires the antimicrobial to target aspects of the pathogens structure or metabolism that are not present, or are not disrupted in the same way, in the host. Bacteria are prokaryotes and have various structures and processes that differ from eukaryotic hosts including the bacterial cell wall and bacterial ribosomes. The bacterial cell wall is the most appealing antibiotic target as it is present in bacteria but not in humans, and antibiotics that target the cell wall should have no effect on eukaryotic cells. Bacterial ribosomes involved in protein synthesis also provide a good target as they differ from cytoplasmic eukaryotic ribosomes. However, the mitochondira of eukaryotic cells contain ribosomes similar to those of prokaryotic cell, and there can be some antibiotic interference in normal eukaryotic cell function if antibiotics targeting protein synthesis are given in excessive amounts. Viruses present a different problem as they are obligate intracellular parasites and antivirals must target the virus or infected cells without affecting non-infected cells to be selectively toxic. Key antiviral targets are viral proteins that are essential to the virus but not to the host eukaryotic cell, such as viral DNA polymerases, including reverse transcriptase, and viral proteases. Selective toxicity is even more difficult to obtain for eukaryotic pathogens such as fungi, and parasitic protozoans and helminths, as they have very similar structures and metabolic processes to the eukaryotic host. The main targets for antifungals are ergosterol in the fungal cell membrane, and the fungal cell wall, as both of these are not present in animal cells, and for antiparasitics against protozoans the main targets are the asexual reproduction stage and folate metabolism. Although there are potential antimicrobial targets in these organisms, many antifungal and antiparasitic drugs have selective toxicity issues and can cause serious side effects.

Explain how sulfa drugs exert their antimicrobial effects. Why is this lethal to the bacterium and how are these drugs selectively toxic?

Sulfa drugs, such as sulfamethoxazole, function by blocking the attachment site for para-aminobenzoic acid (PABA) on an enzyme required for the synthesis of folic acid. The sulfa drug is chemically similar in structure to PABA and competitively inhibits PABA attachment to the enzyme's active site. The incorporation of sulfa instead of PABA blocks the folic acid pathway and this is lethal to bacteria as folic acid is required for the production of purine and pyrimidine nucleotides for nucleic acid synthesis. Sulfa drugs show selective toxicity because unlike bacteria, which must synthesize folic acid for DNA and RNA synthesis, humans obtain preformed folic acid from their diet.

An antimicrobial compound that is activated enzymatically after its introduction into the body is a A. Prodrug B. Antibiotic C. Probiotic D. Competitive inhibitor

A. Prodrug

A pair of antibiotics used to treat vancomycin-resistant enterococcal infections is marketed under the name A. Synercid B. Augmentin C. Timentin D. Primaxin E. Unasyn

A. Synercid

Which of the following antibiotics is mismatched with its mode of action? A. Vancomycin: inhibition of cell wall synthesis in Gram-negative bacteria B. Aminoglycosides: binding to 30S ribosomal subunit and blocking of protein synthesis C. Isoniazid: inhibition of mycolic acid synthesis D. Polymyxin B: disruption of plasma membrane E. Polypeptide antibiotics: inhibition of peptidoglycan polymerization

A. Vancomycin: inhibition of cell wall synthesis in Gram-negative bacteria

Which of the following antibiotics prevents β-lactamase cleavage by binding to it? A. Cephalosporins B. Carbapenems C. Monobactams D. Glycopeptide antibiotics E. Penicillins

B. Carbapenems

Augmentin combines amoxicillin with _____ to overcome enzymatic resistance to the antibiotic by the microbe. A. β-lactamase B. Clavulanic acid C. Transpeptidase D. Sulbactam E. Cilastatin

B. Clavulanic acid

Which of the following is not a drug used for protozoan and helminth infections? A. Metronidazole B. Flucytosine C. Chloroquine D. Piperazine E. Melarsoprol

B. Flucytosine

Which of the following is a mismatched pair? A. Acyclovir (nucleoside analog): herpes simplex virus B. Zanamivir (neuraminidase inhibitor): cytomegalovirus C. Azidothymidine (AZT; nucleoside analog): HIV D. Ribavirin (nucleoside analog): respiratory syncytial virus E. Amantadine (viral un-coating inhibitor): influenza A

B. Zanamivir (neuraminidase inhibitor): cytomegalovirus

Disruption of DNA synthesis occurs if _____ is targeted by antibiotics. A. Bacterial RNA polymerase B. N-acetylglucosamine C. Bacterial topoisomerase D. The A site of the bacterial ribosome

C. Bacterial topoisomerase

Which of the following is not a drug used for fungal infections? A. Azoles B. Foscarnet C. Pentamidine D. Amphotericin B E.Flucytosine

C. Pentamidine

All of the following target the 50S ribosomal subunit except A. Chloramphenicol B. Azithromycin C. Streptomycin D. Erythromycin

C. Streptomycin

Penicillin resistance in bacteria is conferred by the production of A. Lysozyme B. Transglycosylase C. β-lactamase D. N-acetylglucosamine E. Penicillin-binding proteins

C. β-lactamase

Which of the following is not a drug used for viral infections? A. Zanamivir B. Lamivudine (3TC) C. Ritonavir D. Flucytosine E. Ganciclovir

D. Flucytosine

Which of the following is the drug combination of choice when treating tuberculosis? A. Vancomycin, imipenem, aztreonam B. Methicillin, teicoplanin, isoniazid C. Polymyxin B, ethambutol, erythromycin D. Isoniazid, ethambutol, rifampin E. Tetracycline, rifamycin, ciprofloxacin

D. Isoniazid, ethambutol, rifampin

Cephalosporins are more effective than the penicillins against Gram-negative bacteria because they A. Are unable to penetrate the outer membrane through the porin molecules B. Lack a beta-lactam ring C. Have a longer half-life in vivo D. Contain Cilastatin, which prevents destruction of the antibiotic by the kidneys E. Are resistant to β-lactamase enzyme activity

E. Are resistant to β-lactamase enzyme activity

All of the following target the bacterial ribosomal except A. Chloramphenicol B. Erythromycin C. Spectinomycin D. Streptomycin E. Teicoplanin

E. Teicoplanin

Compare the mechanisms of the anti-trypanosomal drugs eflomithine and melasoprol.

Eflomithine is highly effective at treating African sleeping sickness. It inhibits an enzyme that is very stable in Trypanosoma bruceii, but that has a high turnover in humans. This gives the drug a high degree of selective toxicity, having a much greater effect on the parasite than the human host. Melarsoprol, a compound of arsenic, is able to cross the blood-brain barrier and is used to treat trypanomaisis involving the central nervous system. However, arsenic is highly toxic and this drug can cause severe side effects, even death.

Making semi-synthetic antibiotics in the laboratory by altering the side chains of naturally occurring antibiotics is an important approach for generating new antibiotics. Why is a search for new antibiotics needed? Provide examples of new desirable properties conferred on antibiotics through these types of chemical modification.

Naturally derived antibiotics often have a narrow spectrum of activity and chemical alteration of side chains can increase this spectrum. In addition, bacteria can develop resistance to antibiotics, rendering them ineffective, and this is a major reason why new antibiotics are required. There are a number of desirable properties that can be conferred through chemical modification of antibiotics including: a change in antimicrobial activity, increased resistance to stomach acid, increased half-life in the body, an increased spectrum of activity, and increased resistance to bacterial enzymes.