Medchem Lecture 21

Front 1

What are 4 anti fungal classes?

Back 1

Polvenes, allyl aminies, azoles, eschinocandins

Front 2

At the cellular level, the greatest difference between fungal cells and mammalian cells is the what?

Back 2

that fungal cells have cell walls but that mammalian cells do not

Front 3

. Inhibitors of bacterial cell wall biosynthesis, such as ____ and ____ have provided many powerful antibacterial agents with little toxicity to humans.?

Back 3

penicllins and cephalosporins

Front 4

which would be expected to be potent antifungals yet have little human toxicity. Only recently, however, have a few potent inhibitors of ___ ___ ___ ___ have become avaliable for clinical use?

Back 4

of fungal cell wall biosynthesis

Front 5

The difference between fungal and mammalian cells that is most widely exploited, however, is that the cell membranes of fungi and mammals contain different what?

Back 5

sterols

Front 6

Sterols are important structural components of fungal and mammalian cell membranes and are critical to the proper functioning of many what?

Back 6

cell membrane enzymes and ion-transport proteins.

Front 7

Mammalian cell membranes contain what? whereas fungi contain ?

Back 7

cholesterol as the sterol component

ergosterol

Front 8

Although the two sterols are quite similar, the side chains are slightly different, and when three-dimensional models are constructed, the ring system of ergosterol is slightly ____ because of the additional ___ ___ in the B ring

Back 8

flatter

double bonds

Front 9

Most fungal infections are caused primarily by various what?

Back 9

yeasts and molds

Front 10

Yeasts typically grow as what?

Back 10

single oval cells and reproduce by budding

Front 11

Candida albicans and some other pathogenic yeasts also can grow in multicellular chains called what?

Back 11

hyphae

Front 12

. Infection sites may contain both yeast and hyphal forms of the microorganism. True or False

Back 12

True

Front 13

Molds, such as Trichophytonrubrum, one of the causative agents of ringworm, grow in clusters of hyphae called what?

Back 13

mycelium

Front 14

All fungi produce what?

Back 14

spores

Front 15

All fungi produce spores, which may be transported how?

Back 15

by direct contact or through the air

Front 16

Although most topical fungal infections are readily treated, the incidence of life threatening systemic fungal infections, including those caused by yeasts such as ____ and molds such as ___ ____ are increasing and mortality remains high

Back 16

Candida albicans

Aspergillusfumigan

Front 17

The fungal kingdom includes what?

Back 17

yeasts, molds, rusts, and mushrooms

Front 18

Most fungi are what?

Back 18

saprophytic

Front 19

What does saprophytic mean?

Back 19

means that they live on dead organic matter in the soil or on decaying leaves or wood

Front 20

There are relatively few what among the fungi?

Back 20

obligate animal parasites

Front 21

what are obligate animal parasites

Back 21

microorganisms that can only live on mammalian hosts)

Front 22

The obligatory parasites are limited to what?

Back 22

dermatophytes

Front 23

The obligatory parasites are limited to dermatophytesthat have evolved to live on/in the ____ and___ of mammals?

Back 23

kertain-containing hair and skin

Front 24

The obligatory parasites are limited to dermatophytesthat have evolved to live on/in the keratin-containing hair and skin of mammals, where they cause diseases such as what 2?

Back 24

ringworm and athletes foot.

Front 25

IS Ringworm cause by a parasitic worm?

Back 25

No

Front 26

Dermatophytes are fungi causing infections of what 3?

Back 26

skin, hair, and nails

Front 27

The dermatophytes obtain nutrients from attacking what?

Back 27

from attacking the cross-linked structural protein keratin

Front 28

Dermatophytic infections, known as what?

Back 28

tinea

Front 29

Dermatophytic infections, known as tinea, are caused by various species of three genera which are what?

Back 29

Trichophyton, Microsporum, and Epidermophyton)

Front 30

Tineacapitis effects what?

Back 30

hair and scalp

Front 31

tineapedis ?

Back 31

feet

Front 32

tineamanuum?

Back 32

hands

Front 33

tineacruris?

Back 33

groin

Front 34

tineaunguium?

Back 34

fingernails

Front 35

The most common cause of yeast infections is what?

Back 35

Candida albicans

Front 36

The most common cause of yeast infections is Candida albicans, which is part of the normal flora in a significant portion of the population where it resides in the where?(4)

Back 36

oropharynx, gastrointestinal tract, vagina, and surrounding skin

Front 37

Yeast infections commonly occur in what?

Back 37

mucosal tissue when the normal population of flora has been disturbed by treatment of a bacterial infection with an antibiotic or when growth conditions are changed by hormonal fluctuations, such as occur in pregnancy.

Front 38

Thermally Dimorphic Fungi (Endemic Mycoses) are what?

Back 38

saphyophytes

Front 39

Thermally Dimorphic Fungi (Endemic Mycoses) are saprophytes that grow how?

Back 39

in one form at room temperature and in a different form in a human host at 37°C

Front 40

Thermally Dimorphic Fungi (Endemic Mycoses) live where? How do they cause disease?

Back 40

All these organisms live in soil and cause disease through inhalation of contaminated dust.

Front 41

What may transport the organims to different tissue? What can happen?

Back 41

The circulatory system may transport transport the organisms to other tissues, where the resulting systemic infection may be fatal.

Front 42

These fungi are endemic to dry areas of which areas in which countries?

Back 42

southern and southwestern United States and northern Mexico

Front 43

Where is thermally dimorphic fungi prevalent?

Back 43

It is particularly prevalent in the San Joaquin Valley of California, hence the name valley fever.

Front 44

________ is endemic to the Mississippi and Ohio River valleys of the United States, where nearly 90% of the population tests positive for exposure to the organism.

Back 44

Histoplasmacapsulatum

Front 45

What kind of mold species are found worldwide and are virtually ubiquitous in the environment.

Back 45

Aspergillu

Front 46

Because Aspergillus spores are everywhere what is the most common route? What others are possible?

Back 46

inhalation is the most common route of inoculation, but infection through wounds, burns, and implanted devices (e.g., catheters) also is possible

Front 47

_______ aspergillosis is a major source of infection in persons with leukemia and in those receiving organ or bone marrow transplants.

Back 47

Nosocomial(hospital-derived)

Front 48

What is Polyenes MOA?

Back 48

disruption of ergosterol-containing membranes

Front 49

What is Azoles (Imidazoles and Triazoles) MOA?

Back 49

inhibition of ergosterol biosynthesis (14α-demethylase enzyme)

Front 50

What is Allyl amines MOA?

Back 50

inhibition of ergosterol biosynthesis (squaleneepoxidase enzymes)

Front 51

What is Morpholines MOA?

Back 51

inhibition of ergosterol biosynthesis (Δ14-reductase and Δ8,Δ7-isomerase enzymes)

Front 52

What is Eschinocandins MOA?

Back 52

Inhibitors of cell wall biosynthesis (β-1,3-glucan synthase enzyme)

Front 53

Polyeneshave an affinity for what membranes?

Back 53

sterol-containing membranes

Front 54

The membranes of cells treated with polyenes become leaky, and eventually, the cells die because of the loss of what?

Back 54

essential cell constituents, such as ions and small organic molecules

Front 55

. Polyenes have a demonstrably higher affinity for membranes containing ___ over ____ containing membranes

Back 55

ergosterol over cholesterol

Front 56

The last nonsteroidal precursor to both ergosterol and cholesterol is the hydrocarbon _____?

Back 56

squalene.

Front 57

Squalene is converted to ____ by th eenzyme ___?

Back 57

squaleneepoxideby the enzyme squaleneepoxidase (1).

Front 58

Squaleneepoxide is then cyclized to ___?

Back 58

lanosterol, the first steroid in the biosynthetic pathway

Front 59

Lanosterol is demethylated by what?

Back 59

14α-demethylase (2).

Front 60

Conversion of the side chain of lanosterol to the side chain of ___ involves action of ______ and _____

Back 60

ergosterol involves the acttion of Δ14-reductase (3) and Δ8,Δ7-isomerase (4) enzymes.

Front 61

All the azoles (imidazoles or triazoles) act by inhibiting what?

Back 61

ergosterol biosynthesis through inhibition of the 14α-demethylase enzyme (Site 2).

Front 62

The mechanism of action of the azoleagricultural antifungalsis identical to that of the agents used for what infections?

Back 62

for mammalian infections (inhibiting ergosterol biosynthesis)

Front 63

All of the allyl amines act by through the inhibition of the enzyme

Back 63

squaleneepoxidase (Site 1).

Front 64

What 3 drugs are not used to treat human disease but have wide utility in protecting crops from phytopathogenic fungi.

Back 64

he morpholines, fenpropimorph and tridemorph,

Front 65

_____ is the only drug in this class that is employed clinically in the treatment of human fungal infections?

Back 65

Amorolfine

Front 66

. Morpholine antifungals inhibit ergosterol biosynthesis by acting on the enzymes ____ and ____?

Back 66

Δ14-reductase and Δ8,Δ7-isomerase (Site 3 and 4).

Front 67

Fungal cells have a cell wall and mammalian cells do not. True or False

Back 67

True

Front 68

____ interfere with cell wall biosynthesis through inhibition of the enzyme ____ _____

Back 68

Echinocandins

β-1,3-glucan synthase

Front 69

β-Glucan is an important polymer component of many what>

Back 69

fungal cell walls, and reduction in the glucan content severely weakens the cell wall, leading to rupture of the fungal cell.

Front 70

_____ is an iodinated acetylene active against dermatophytes

Back 70

Haloprogin

Front 71

Haloprogin is only used for what?

Back 71

topical applications

Front 72

Haloprogin has been demonstrated to interfere with what 2 components?

Back 72

with DNA biosynthesis and cell respiration

Front 73

______ is a hydroxylatedpyridinone that is employed for superficial dermatophytic infections, principally onychomycosis

Back 73

Ciclopirox

Front 74

Ciclopirox has a unique mechanism of action through what? What dose it cause?

Back 74

chelation of polyvalent cations, such as Fe3+, which causes inhibition of a number of metal-dependent enzymes within the fungal cell

Front 75

. Although ciclopirox has been available for more than 30 years, a new formulation of an 8% lacquer has been recently introduced for treating what?

Back 75

Nail Infections

Front 76

What are 3 antimycobacterial classes?

Back 76

Antituberculin drugs

MAC therapy

Leprostatic drugs

Front 77

What 2 drugs are under the MAC Therapy Class?

Back 77

Azithromycin
Clarithromycin

Front 78

What 4 drugs are under the leprostatic drugs?

Back 78

Clofazimine
Dapsone
Rifampin
Thalidomide

Front 79

what are AntimycobacterialsTherapeutic Options?

Back 79

Antituberculins (TB)
First Line Agents
Second Line Agents

MAC Drug Therapy (Mycobacterium Avium–Intracellulare Complex)

Leprostatics (Leprosy)

Front 80

Mycobacteria are a genus of acid-fast bacilli belonging to the what?

Back 80

Mycobacteriaceae

Front 81

Mycobacteria are a genus of acid-fast bacilli belonging to the Mycobacteriaceae, which include the organisms responsible for what?

Back 81

for uberculosis and leprosy as well as a number of other, less common diseases.

Front 82

Characteristic of mycobacteria is the fact that these organisms tend to be what 3 charateristics?

Back 82

slow-growing,
difficult to stain,
and when they are stained with basic dye, can resist decolorization with acid alcohol.

Front 83

Mycobacteria staining characteristics relate to the what?

Back 83

abnormally high lipid content of the cell wall

Front 84

what holds the secret to many of the characteristics of this genus of organisms?

Back 84

the cell wall or cell envelope of the mycobacterium

Front 85

The cell envelope is unique in both ___ and __?

Back 85

structure and complexity

Front 86

It has been suggested that the cell envelope is responsible for mycobacterium for what 5 components?

Back 86

pathogenicity or virulence, multiple drug resistance, cell permeability, immunoreactivity and inhibition of antigen responsiveness, as well as disease persistence and recrudescence

Front 87

The mycobacterial cell envelope contains, on the interior surface what?

Back 87

a plasma membrane similar to that found in most bacteria.

Front 88

The mycobacterial cell envelope contains, on the interior surface, a plasma membrane similar to that found in most bacteria. What appears next.

Back 88

A conventional peptidoglycan layer affording the organism rigidity

Front 89

The peptidoglycan layer is composed of what?

Back 89

alternating N-acetyl-D-glucosamines (Glu) linked to N-glycoyl-D-muramic acids (Mur) through 1–4 linkages that, in turn, is attached to the peptido chain of D-alanine (A), D-glutamine (G), meso-diaminopimelic acid (DP), and L-alanine (A).

Front 90

How is TB characterized?

Back 90

as a chronic bacterial infection caused by Mycobacterium tuberculosis, an acid-fast, aerobic bacillus with the previously discussed, unusual cell wall.

Front 91

The cell wall in TB has high what? What does this result in a high degree of?

Back 91

The cell wall has a high lipid content, resulting in a high degree of hydrophobicity and resistance to alcohol, acids, alkali, and some disinfectants.

Front 92

After staining with a dye, the M. tuberculosis cell wall cannot subsequently be what? What does this end up being?

Back 92

decolorized with acid wash

thus the characteristic of being an acid-fast bacillus.

Front 93

It is estimated that today, one-third to one-half of the world population is infected with what?

Back 93

M. tuberculosis, leading to approximately 6% of all deaths worldwide (~2 million deaths).

Front 94

Mycobacterium tuberculosis is transmitted primarily via what route?

Back 94

respiratory

Front 95

Mycobacterium tuberculosis appears in what?

Back 95

in water droplets expelled during coughing, sneezing, or talking

Front 96

TB is a disease that mainly affects what?

Back 96

lungs (80-85% of cases)

Front 97

TB is a disease that mainly affects the lungs (80–85% of the cases), but M. tuberculosis can spread through the what?

Back 97

bloodstream and the lymphatic system to the brain, bones, eyes, and skin (extrapulmonary TB).

Front 98

___ or ___ may result from the infection and may lie dormant, encapsulated in a fibrotic lesion, for years and then reappear later.

Back 98

Granulomas or tubercles

Front 99

Patients with HIV infection and TB are ____ more likely of developing an active infection than noninfected patients.

Back 99

100-fold

Front 100

what are are atypical acid-fast bacilli that are ubiquitous in the environment and usually considered to be nonpathogenic in healthy individuals.?

Back 100

Mycobacterium Avium–Intracellulare Complex

Front 101

__ ___ ___ - ___ ___ is the most common bacterial opportunistic infection seen in patients with AIDS and the third most common opportunistic infection reported in patients with AIDS.

Back 101

Disseminated Mycobacterium avium–intracellulare complex (MAC)

Front 102

Today, approximately half of all patients with AIDS develop an infection caused by what?

Back 102

MAC

Front 103

The MAC organisms grow within what?

Back 103

macrophages

Front 104

____ is recognized as a chronic granulomatous infection caused by Mycobacterium leprae.

Back 104

Leprosy (Hansen's Disease)

Front 105

Leprosy may consist of what 3 components?

Back 105

lepromatous leprosy, tuberculoid leprosy, or a condition with characteristics between these two poles and referred to as borderline leprosy.

Front 106

Where is Leprosy more common?

Back 106

more common in tropical countries but is not limited to warm climate regions

Front 107

What is Leprosy's incubation period?

Back 107

The incubation period usually is three to five years.

Front 108

How is the Leprosy spread?

Back 108

Person-to-person contact appears to be the means by which the disease is spread, with entrance into the body occurring through the skin or the mucosa of the upper respiratory tract.

Front 109

What regions are the most susceptible to attack by leprosy?

Back 109

Skin and peripheral nerves

Front 110

_____ is generally considered to be the primary drug for treatment of M. tuberculosis

Back 110

Isoniazid (INH)

Front 111

It generally is recognized that INH is a pro-drug that is activated through what? By what kind of enzyme?

Back 111

an oxidation reaction catalyzed by an endogenous enzyme.

Front 112

Which enzyme exhibits catalase-peroxidase activity

Back 112

katG

Front 113

katG converts INH to a reactive species capable of what?

Back 113

acylationof an enzyme system found exclusively in M. tuberculosis.

Front 114

What are TB 1st line agents?

Back 114

Rifamycin Antibiotics

Front 115

The rifamycins inhibit bacterial____ by bidning to the __ subunit of the enzyme and are highly active against what?

Back 115

DNA-dependent RNA polymerase (DDRP) by binding to the β-subunit of the enzyme and are highly active against rapidly dividing intracellular and extracellular bacilli.

Front 116

With the introduction of Rifampin (RIF) in 1967, the duration of combination therapy for the treatment of TB was significantly ____?

Back 116

reduced (from 18 to 9 months).

Front 117

RIF is nearly always used how?

Back 117

in combination with one or more other antituberculin agents.

Front 118

Rif is a ____ _____

Back 118

P450 Inducer

Front 119

the CDC has recommended avoidance of RIF in treatment of what patients?

Back 119

HIV-infected

Front 120

What is another TB first-line agent

Back 120

Pyrazinamide(pyrazinecarboxamide)

Front 121

Pyrazinamide(pyrazinecarboxamide) was discovered while investigating analogues of _____?

Back 121

nicotinamide.

Front 122

Pyrazinamide is a ______ of nicotinamide

Back 122

bioisostere

Front 123

Pyrazinamide is a bioisostere of nicotinamide and possesses what?

Back 123

bactericidal action against Mycobacterium tuberculosis.

Front 124

Recent findings suggest that pyrazinamide may be active either totally or in part as a __-___?

Back 124

pro-drug

Front 125

Pyrazinamide has gained acceptance as an essential component in combination therapy for the treatment of TB. What is it a component of?

Back 125

(Rifaterwith INH and RIF).

Front 126

What is another 1st line TB agent?

Back 126

Ethambutol (EMB)

Front 127

Mycobacterium have a unique outer envelop consisting of ___ and ___?

Back 127

arabinofuranoseand galactose(AG)

Front 128

Mycobacterium have a unique outer envelop consisting of arabinofuranoseand galactose(AG), which is covalently attached to the peptidoglycan and an intercalated framework of ____

Back 128

lipoarabinomannan (LAM).

Front 129

The AG portion of the cell wall is highly branched and contains what?

Back 129

distinct segments of galactan and distinct segments of arabinan

Front 130

Ethambutol (EMB) mimics what?

Back 130

arabinan

Front 131

Ethambutol (EMB) mimics arabinan, resulting in a buildup of the arabinan precursor ____

Back 131

β-D-arabinofuranosyl-1-monophosphoryldecaprenol

Front 132

Ethambutol (EMB) mimics arabinan, resulting in a buildup of the arabinan precursor β-D-arabinofuranosyl-1-monophosphoryldecaprenol and, as a result, blockage of the synthesis of both ____ and __

Back 132

AG and LAM.

Front 133

What is another TB First Line agent?

Back 133

Streptomycin (STM)

Front 134

_____ was first isolated by Waksman and coworkers in 1944 and represented the first biologically active aminoglycoside.

Back 134

Streptomycin (STM)

Front 135

Streptomycin is able to diffuse across what of what?

Back 135

the outer membrane of Mycobacterium tuberculosis

Front 136

Streptomycin is able to diffuse across the outer membrane of Mycobacterium tuberculosis and, ultimately, to penetrate the ___ ___ and ___-____ process?

Back 136

cytoplasmic membrane through an electron-dependent process.

Front 137

What is a TB-Second-Line agent?

Back 137

Ethionamide

Front 138

The synthesis of analogues of isonicotinamide resulted in the discovery of ____ and a homologue in which the ethyl group is replaced with a ____?

Back 138

ethionamide

propyl (prothionamide).

Front 139

Both ethionamide and propyl (prothionamide) compounds have proven to be bactericidal against

Back 139

Mycobacterium tuberculosis and Mycobacterium leprae.

Front 140

Evidence has been presented suggesting that the mechanism of action of ethionamide is similar to that of INH, where ethionamide is considered to be a pro-drug, which is converted via oxidation by catalase-peroxidase to an active acylating agent, _____, which in turn inactivates the ___?

Back 140

thionamidesulfoxide

inhAenoylreductase enzyme

Front 141

What is another TB - Second-Line Agents?

Back 141

Cycloserine

Front 142

What is the active form of cycloserine?

Back 142

D-Cycloserine

Front 143

D-Cycloserineis considered to be the active form of the drug, having its action associated with the ability to inhibit two key enzymes, ____ and ____

Back 143

D-alanineracemase (1) and D-alanineligase (2).

Front 144

D-Alanine is an important component of the what?

Back 144

peptidoglycan portion of the mycobacterial cell wall.

Front 145

What is another TB - Second-Line Agents ?

Back 145

Capreomycin

Front 146

Capreomycinis a mixture of four what?

Back 146

four cyclic polypeptides,

Front 147

Capreomycinis a mixture of four cyclic polypeptides, of which ____ and ___ make up 90% of the mixture

Back 147

capreomycinIA and IB

Front 148

Capreomycin is produced by what? What antibiotic is it similar to?

Back 148

Streptomycescapreolusand is quite similar to the antibiotic viomycin

Front 149

Viomycin is a potent inhibitor of what?

Back 149

protein synthesis,

Front 150

Viomycin is a potent inhibitor of protein synthesis, particularly that which depends on ___ at the ___ ribosome?

Back 150

mRNA at the 70S ribosome.

Front 151

Viomycin blocks chain what?

Back 151

elongation

Front 152

Viomycin blocks chain elongation how?

Back 152

binding to either or both the 50S or 30S ribosomal subunits.

Front 153

What kind of drug is viomycin?

Back 153

a second-line bacteriostatic antituberculin drug, it is reserved for “resistant” infections and cases of treatment failure.

Front 154

Should the drug be given as a single agent?

Back 154

No

Front 155

What should capreomycin be used in combo with?

Back 155

EMB or INH.

Front 156

The 1997 guidelines for prophylaxis of MAC advise that all adults and adolescents with HIV infection and a CD4 lymphocyte count of less than 50 cells/mL receive what drugs and what dosing?

Back 156

clarithromycin, 500 mg b.i.d., or azithromycin, 1200 mg once a week.

Front 157

For treatment of MAC, it is recommended that a combination therapy be used that includes at least two drugs. Either ___ or ___ plus ___ for life

Back 157

either clarithromycin or azithromycin plus EMB for life).

Front 158

Other drugs that can be added to the combination consist of what 3?

Back 158

rifabutin, fluoroquinolones, and amikacin.

Front 159

What are ineffective in the treatment of disseminated MAC?

Back 159

that INH and pyrazinamide

Front 160

What is a Leprostatic?

Back 160

Sulfones

Front 161

The ___ represent the major class of agents used to treat leprosy.

Back 161

diarylsulfones

Front 162

The initial discovery of the sulfones came about as a result of studies directed at exploring what?

Back 162

the SAR of sulfonamides

Front 163

_____ was first introduced into the treatment of leprosy in 1943.

Back 163

Dapsone,

Front 164

Dapsone is what kind of agent?

Back 164

a bacteriostatic agent,

Front 165

Dapsone, a bacteriostatic agent, is thought to act in a manner similar to that of the sulfonamides—namely, through what kind of inhibition? Inhibition of what?

Back 165

competitive inhibition of p-aminobenzoic acid incorporation into folic acid (as with the sulfonamide antibiotics).

Front 166

Bacteria synthesize __ ___ but host cells do not?

Back 166

folic acid

Front 167

What co-administration will inactivate dapsone?

Back 167

coadministration of dapsone and p-aminobenzoic acid

Front 168

What is the final leprostatic?

Back 168

Thalidomide

Front 169

The development of painful, tender, inflamed, subcutaneous nodules that may last a week or two but may reappear and last for long periods is seen in a number of diseases. In the case of leprosy, the condition is referred to as ____?

Back 169

erythemanodosumleprosum (ENL).

Front 170

erythemanodosumleprosum (ENL) has been successfully treated with what?

Back 170

Thalidomide

Front 171

The mechanism whereby thalidomide produces relief is thought to be associated with the drug's ability to control ____ ____

Back 171

inflammatory cytokines.

Front 172

What kind of agent is thalidomide?

Back 172

very potent teratogenic agent

Front 173

Thalidomide can be safely used in what kind of women?

Back 173

postmenopausal women, but strict controls are required for women of childbearing age.