10

Question 1

antimicrobials

Answer 1

Drugs that act against diseases
are called chemotherapeutic agents. Examples include insulin,
anticancer drugs, and drugs for treating infections—called
antimicrobial agents (antimicrobials)

Question 2

chemotherapy

Answer 2

ehrlich proposed the term chemotherapy to describe
the use of chemicals that would selectively kill pathogens
while having little or no effect on a patient. He wrote of “magic
bullets” that would bind to receptors on germs to bring about
their death while ignoring host cells, which lacked the receptor
molecules.

Question 3

penicillin

Answer 3

British bacteriologist
Alexander Fleming reported the antibacterial action
of penicillin released from Penicillium) mold,
which creates a zone where bacteria don’t grow

Question 4

sulfanilamide

Answer 4

discovered by german chemist Gerhard Domagk in 1932; the first
practical antimicrobial agent efficacious in treating a wide array
of bacterial infections.

Question 5

waksman

Answer 5

discovered other microorganisms
that are sources of useful antimicrobials; coined the term antibiotics to describe
antimicrobial agents that are produced naturally by an
organism

Question 6

In common usage today, “antibiotic”

Answer 6

denotes an antibacterial
agent, including synthetic compounds and excluding agents
with antiviral and antifungal activity

Question 7

semisynthetics

Answer 7

Other scientists produced semisynthetics—chemically altered
antibiotics—that are more effective, longer lasting, or easier
to administer than naturally occurring antibiotics. Antimicrobials
that are completely synthesized in a laboratory are called synthetics.
Most antimicrobials are either natural or semisynthetic

Question 8

selective toxicity

Answer 8

As Ehrlich foresaw, the key to successful chemotherapy against
microbes is selective toxicity; that is, an effective antimicrobial
agent must be more toxic to a pathogen than to the pathogen’s
host. Selective toxicity is possible because of differences in structure
or metabolism between the pathogen and its host.

Question 9

peptidoglycan structure

Answer 9

huge macromolecule composed
of polysaccharide chains of alternating N-acetylglucosamine
(NAG) and N-acetylmuramic acid (NAM) molecules that are
cross-linked by short peptide chains extending between NAM
subunits

Question 10

To enlarge or divide, a cell must synthesize

more peptidoglycan by

Answer 10

adding new NAG and NAM
subunits to existing NAG-NAM chains, and the new NAM
subunits must then be bonded to neighboring NAM subunits

Question 11

To enlarge or divide, a cell must synthesize

more peptidoglycan by

Answer 11

adding new NAG and NAM
subunits to existing NAG-NAM chains, and the new NAM
subunits must then be bonded to neighboring NAM subunits

Question 12

beta lactams

Answer 12

Many common antibacterial agents act by preventing the
cross-linkage of NAM subunits. Most prominent among these
drugs are beta-lactams, which are antimicrobials whose functional portions
are called beta-lactam rings. Betalactams
inhibit peptidoglycan formation by irreversibly binding
to the enzymes that cross-link NAM subunits.

Question 13

v, c

Answer 13

Other antimicrobials such as vancomycin and cycloserine, a semisynthetic, disrupt cell
wall formation in a different manner. They directly interfere
with particular alanine-alanine bridges that link the NAM subunits
in many Gram-positive bacteria. Those bacteria that lack
alanine-alanine crossbridges are naturally resistant to these
drugs.

Question 14

bacitracin

Answer 14

Still another drug that prevents cell wall formation,
bacitracin (bas@i@tra´sin), blocks the transport of NAG and NAM
from the cytoplasm out to the wall.

Question 15

drugs that prevent cell wall formation

Answer 15

Like beta-lactams, vancomycin,
cycloserine, and bacitracin result in cell lysis due to the
effects of osmotic pressure.
Since all these drugs prevent bacteria from increasing the
amount of cell wall material but have no effect on existing peptidoglycan,
they are effective only on bacterial cells that are
growing or reproducing; dormant cells are unaffected

Question 16

mycobacterium structure

Answer 16

notably the agents of leprosy and tuberculosis, are characterized
by unique, complex cell walls that have a layer of arabinogalactan–
mycolic acid in addition to the usual peptidoglycan of prokaryotic
cells.

Question 17

mycobacterium antimicrobials

Answer 17

isonizaid or INH and ethambutol disrupt the formation of this extra layer. Mycobacteria
typically reproduce only every 12 to 24 hours, in part because
of the complexity of their cell walls, so antimicrobial agents
that act against mycobacteria must be administered for months
or even years to be effective.

Question 18

echinocandins

Answer 18

Fungal cell walls are composed of various polysaccharides containing
a sugar, 1,3-D-glucan, that is not found in mammalian
cells. A new class of antifungal drugs called echinocandins,
among them caspofungin, inhibit the enzyme that synthesizes
glucan; without glucan, fungal cells cannot make cell walls,
leading to osmotic rupture.

Question 19

However, prokaryotic ribosomes differ from

eukaryotic ribosomes in structure and size:

Answer 19

Prokaryotic ribosomes
are 70S and composed of 30S and 50S subunits, whereas
eukaryotic ribosomes are 80S with 60S and 40S subunits
- euk mitochondria also contain 70S ribosomes

Question 20

microbials that target the prok subunits

Answer 20

30S: aminoglycosides and tetracyclines; 50S: chloramphenicol, lincosamides, streptogramins, macrolides

Question 21

aminoglycosides

Answer 21

change the shape of the 30S subunit, making it impossible for the
ribosome to read the codons of mRNA correctly

Question 22

tetracyclines

Answer 22

Other aminoglycosides and tetracyclines block
the tRNA docking site (A site), which then prevents the incorporation
of additional amino acids into a growing polypeptide

Question 23

chloramphenicol

Answer 23

Chloramphenicol and similar drugs block the enzymatic

site of the 50S subunit, which prevents

Question 24

Lincosamides, streptogramins, and macrolides

Answer 24

bind to a different portion
of the 50S subunit, preventing movement of the ribosome from
one codon to the next; as a result, translation is
frozen and protein synthesis is halted.

Question 25

antisense nucleic acids

Answer 25

These RNA or single-stranded
DNA molecules are designed to be complementary to specific
mRNA molecules of pathogens. They block ribosomal subunits
from attaching to that mRNA with no effect on human
mRNA.

Question 26

Oxazolidinones

Answer 26

antimicrobial drugs that work to stop

protein synthesis by blocking initiation of translation

Question 27

polyenes

Answer 27

disrupt the cytoplasmic membrane of a targeted cell,
often by forming a channel through the membrane, damaging
its integrity.
- fungicidal
because they attach to ergosterol, a lipid constituent of fungal
membranes (Figure 10.5b), in the process disrupting the membrane
and causing lysis of the cell. The cytoplasmic membranes
of humans are somewhat susceptible to amphotericin
B because they contain cholesterol, which is similar to ergosterol,
though cholesterol does not bind amphotericin B as well
as does ergosterol.

Question 28

azoles

Answer 28

antifungal drugs that disrupt
cytoplasmic membranes. They act by inhibiting the synthesis
of ergosterol; without ergosterol, the cell’s membrane does not
remain intact, and the fungal cell dies. Azoles and allylamines
are generally harmless to humans because human cells do not
manufacture ergosterol.

Question 29

paba metabolism

Answer 29

Many organisms, including some pathogens, enzymatically
convert PABA into dihydrofolic acid and then dihydrofolic
acid into tetrahydrofolic acid (THF), a form of folic acid that is
used as a coenzyme in the synthesis of purine and pyrimidine
nucleotides

Question 30

sulfonamides

Answer 30

act as antimetabolic drugs because they are
structural analogs of—that is, are chemically very similar to—
para-aminobenzoic acid. As analogs of PABA, sulfonamides
compete with PABA molecules for the active site of the enzyme
involved in the production of dihydrofolic acid (Figure 10.6c).
This competition leads to a decrease in the production of THF
and thus of DNA and RNA.

Question 31

human paba metabolism

Answer 31

humans do not synthesize THF from PABA; instead,
we take simple folic acids found in our diets and convert
them into THF. As a result, human metabolism is unaffected by
sulfonamides.

Question 32

trimethoprim

Answer 32

Another antimetabolic agent, trimethoprim, also interferes
with nucleic acid synthesis. However, instead of binding to the
enzyme that converts PABA to dihydrofolic acid, trimethoprim
binds to the enzyme involved in the conversion of dihydrofolic
acid to THF, the second step in this metabolic pathway

Question 33

antivirals

Answer 33

Some viruses of eukaryotes are uncoated as a result of the acidic environment within phagolysosomes. Amantadine,
rimantadine, and weak organic bases can neutralize the acid of
phagolysosomes and thereby prevent viral uncoating; thus,
these are antiviral drugs.

Question 34

allylamines

Answer 34

antifungal drugs that disrupt
cytoplasmic membranes. They act by inhibiting the synthesis
of ergosterol; without ergosterol, the cell’s membrane does not
remain intact, and the fungal cell dies. Azoles and allylamines
are generally harmless to humans because human cells do not
manufacture ergosterol.

Question 35

nucleotide/side analogs

Answer 35

molecules with
structural similarities to the normal nucleotide building
blocks of nucleic acids. their structures enable them to be incorporated into the DNA or RNA
of pathogens, where they distort the shapes of the nucleic
acid molecules and prevent further replication, transcription,
or translation.
- most often used against viruses because viral DNA polymerases are
tens to hundreds of times more likely to incorporate nonfunctional
nucleotides into nucleic acids than is human DNA polymerase.
also viruses faster nucleic acid synthesis

Question 36

quinolones

Answer 36

The synthetic drugs called quinolones, including fluoroquinolones,
are unusual because they are active against prokaryotic
DNA specifically. These antibacterial agents inhibit DNA
gyrase, an enzyme necessary for correct coiling and uncoiling
of replicating bacterial DNA; they typically have little effect on
eukaryotes or viruses.

Question 37

rifampin

Answer 37

Other antimicrobial agents function by binding to and inhibiting
the action of RNA polymerases during the synthesis of
RNA from a DNA template. Several drugs, including rifampin
(rif´am@pin), bind more readily to prokaryotic RNA polymerase
than to eukaryotic RNA polymerase; as a result, rifampin is
more toxic to prokaryotes than to eukaryotes.

Question 38

attachment antagonists

Answer 38

Attachment of viruses can be blocked by peptide and sugar
analogs of either attachment or receptor proteins. When these
sites are blocked by analogs, viruses can neither attach to nor
enter their hosts’ cells. The use of such substances, called attachment
antagonists, is an exciting new area of antimicrobial drug
development.

Question 39

spectrum of action

Answer 39

The number of different kinds of pathogens a drug acts against
is known as its spectrum of action

Question 40

broad-spectrum drugs

Answer 40

The use of broad-spectrum antimicrobials is not always as
desirable as it might seem. Broad-spectrum antimicrobials can
also open the door to serious secondary infections by transient
pathogens or superinfections by members of the normal microbiota
unaffected by the antimicrobial.

Question 41

microbial antagonism

Answer 41

the
killing of normal microbiota reduces microbial antagonism, the
competition between normal microbes and pathogens for nutrients
and space. Microbial antagonism reinforces the body’s
defense by limiting the ability of pathogens to colonize the
skin and mucous membranes.

Question 42

Diffusion

susceptibility tests enable scientists to classify pathogens as

Answer 42

susceptible, intermediate, or resistant to each drug.

Question 43

Diffusion susceptibility tests

Answer 43

also known as Kirby-Bauer tests,
involve uniformly inoculating a Petri plate with a standardized
amount of the pathogen in question. Then small disks of paper
containing standard concentrations of the drugs to be tested are
firmly arranged on the surface of the plate. The plate is incubated,
and the bacteria grow and reproduce to form a “lawn”
everywhere except the areas where effective antimicrobial
drugs diffuse through the agar. After incubation, the plates are
examined for the presence of a zone of inhibition—that is, a
clear area where bacteria do not grow (Figure 10.9). A zone of inhibition
is measured as the diameter (to the closest millimeter)
of the clear region.

Question 44

MIC

Answer 44

Once scientists identify an effective antimicrobial agent, they
quantitatively express its potency as a minimum inhibitory
concentration (MIC), often using the unit μg/ml. As the name
suggests, the MIC is the smallest amount of the drug that will
inhibit growth and reproduction of the pathogen. The MIC can
be determined via a broth dilution test

Question 45

broth dilution test

Answer 45

a standardized
amount of bacteria is added to serial dilutions of antimicrobial
agents in tubes or wells containing broth. After incubation,
turbidity (cloudiness) indicates bacterial growth; lack of turbidity
indicates that the bacteria were either inhibited or killed
by the antimicrobial agent

Question 46

MBC test

Answer 46

Similar to the MIC test is a minimum bactericidal concentration
(MBC) test, though an MBC test determines the amount of drug
required to kill the microbe rather than just the amount to inhibit
it, as the MIC does. In an MBC test, samples taken from
clear MIC tubes (or, alternatively, from zones of inhibition from
a series of diffusion susceptibility tests) are transferred to plates
containing a drug-free growth medium (Figure 10.12). The appearance
of bacterial growth in these subcultures after appropriate
incubation indicates that at least some bacterial cells survived that concentration of the antimicrobial drug and were
able to grow and multiply once placed in a drug-free medium.

Question 47

MBC

Answer 47

Any drug concentration at which growth occurs in subculture
is bacteriostatic, not bactericidal, for that bacterium. The lowest
concentration of drug for which no growth occurs in the subcultures
is the minimum bactericidal concentration (MBC).

Question 48

IM v IV

Answer 48

IM administration via a hypodermic needle allows a drug to
diffuse slowly into the many blood vessels within muscle tissue, but
the concentration of the drug in the blood is never as high as that
achieved by IV administration, which delivers the drug directly
into the bloodstream through either a needle or a catheter (a plastic
or rubber tube). The amount of a drug in the blood is initially very
high for the IV route, but the concentration can rapidly diminish as
the liver and kidneys remove the drug from the circulation, unless the drug is continuously adminsitered

Question 49

Another aspect of chemotherapy that physicians must consider
is the possibility of adverse side effects. These fall into three main
categories

Answer 49

toxicity, allergies, and disruption of normal microbiota.

Question 50

TI

Answer 50

Researchers are able to estimate the safety of an antimicrobial
drug by calculating the drug’s therapeutic index (TI),
which is essentially a ratio comparing the dose of the drug
that a patient can tolerate to the drug’s effective dose. The
higher the TI, the safer the drug.

Question 51

therapeutic range

Answer 51

Clinicians refer to a drug’s
therapeutic range (therapeutic window), which is the range
of concentrations of the drug that are effective without being
excessively toxic.

Question 52

allergies

Answer 52

In addition to toxicity, some drugs trigger allergic immune
responses in sensitive patients. Although relatively rare, such
reactions may be life threatening, especially in an immediate,
violent reaction called anaphylactic shock.

Question 53

Disruption of Normal Microbiota

Answer 53

Drugs that disrupt normal microbiota and their microbial antagonism
of opportunistic pathogens may result in secondary infections.
In instances when a member of the normal microbiota is not
affected by a drug, it is an opportunistic pathogen and can overgrow,
causing a disease.

Question 54

acquiring ressitance

Answer 54

Among bacteria, individual
cells can acquire such resistance in two ways: through
new mutations of chromosomal genes or by acquiring resistance genes on extrachromosomal pieces of DNA called R plasmids
(or R factors) via the processes of horizontal gene transfer—
transformation, transduction, or conjugation.

Question 55

beta lactamases

Answer 55

Resistant cells may produce an enzyme that destroys or
deactivates the drug. This common mode of resistance
is exemplified by beta-() lactamases (penicillinases),
which are enzymes that break the beta-lactam rings of
penicillin and similar molecules, rendering them inactive

Question 56

Multiple-drug-resistant pathogens

Answer 56

(erroneously called
superbugs in the popular press) are resistant to three or more
types of antimicrobial agents.

Question 57

cross resistanc e

Answer 57

Resistance to one antimicrobial agent may confer resistance
to similar drugs, a phenomenon called cross resistance. Cross
resistance typically occurs when drugs are similar in structure.

Question 58

Finally, scientists can combat resistant strains by developing
new drugs

Answer 58

in some cases by adding novel side chains to the
original molecule. In this way, scientists develop semisynthetic
second-generation drugs. If resistance develops to these drugs,
third-generation drugs may be developed to replace them