LECTURE 8. ANTIMICROBIAL DRUGS.
THE DISCOVERY OF ANTIMICROBIAL DRUGS
THE HISTORY OF ANTIMICROBIAL CHEMOTHERAPY ORIGINATES FROM PAUL ERLICH
 Ehrlich believed in a selective toxicity for specific chemicals against
microbes as he observed that specific dyes (like aniline) would stain specific
bacterial species. Therefore, there must be specific chemicals that would be toxic
to these species. This selective toxicity concept was developed in the early 1900s
when Ehrlich thought he could discover those specific chemicals that would seek out
and destroy specific disease organisms in infected tissues without harming those
tissues.
 Ehrlich and his staff had synthesized hundreds of arsenic-phenol compounds. One
of Ehrlich’s collaborators, Sahachiro Hata, discovered that compound #606 in the
series, arsphenamine, is active against the syphilis spirochete Treponema
pallidum. In 1910, they gave it a brand name Salvarsan (because it offered
salvation from syphilis and contained arsenic) and tranferred the drug to doctors for
use against syphilis.
 The structure of salvarsan remained controversial
until 2005, when professor Brian K. Nicholson from New
Zealand reported that Salvarsan is in fact a mixture of
cyclic As-As bonded species. This mixture of (RAs)3 and
(RAs)5 serves to slowly release RAs(OH)2, the oxidized
species that likely gives rise to Salvarsan's antisyphilis
properties.
Angew. Chem. Int. Ed. 2005, 44, 941
THE DISCOVERY OF ANTIMICROBIAL DRUGS
1939 NOBEL PRICE IN PHYSIOLOGY AND MEDICINE WENT TO GERHARD DOMAGK FOR SULFONAMIDES
 In 1932, another product of synthetic dye industry, a red dye, trademarked as
Prontosil, turned out to be antibacterial drug in vivo, while it had no apparent effect on
bacterial cells in culture. German pathologist and bacteriologist Gerhard Domagk
demonstrated a pronounced inhibitory effect of Prontosil on staphylococci,
streptococci, and other gram(+) bacterial species in animals. It was later discovered
that blood enzymes split the Prontosil molecule, producing a smaller molecule called
sulfanilamide; this breakdown product acted against the infecting streptococci.
Thus, the discovery of sulfanilamide, the first sulfa drug, was based on
luck as well as scientific effort.
In February 1935, Domagk injected the dye into
his daughter Hildegard, who had become gravely ill
with septicemia after pricking her finger with a
needle. Her condition gradually improved and her
arm did not have to be amputated.
 For his discovery, Domagk was awarded the 1939
Nobel Prize in Physiology or Medicine.
THE DISCOVERY OF ANTIMICROBIAL DRUGS
AN ADVENT OF ANTIBIOTICS
 In 1928, Alexander Fleming, a British scientist, working with cultures of
Staphylococcus discovered that colonies growing near a contaminating mold
were disappearing. He found the mold was a species of Penicillium, and it
was indeed producing a bacteria-killing substance; he called this penicillin.
Even though Fleming was unable to purify penicillin, he showed its
remarkable efficiency in killing many different kinds of bacteria and could be
injected into rabbits and mice without adverse effects.
Nobel Prize 1945
 Approximately 10 years after Fleming’s discovery, two other scientists in Britain, Ernst Chain and Howard Florey,
successfully purified penicillin. Several different penicillins were found in the Penicillium cultures, and were designated
alphabetically. Penicillin G (or benzyl penicillin) was found to be the most suitable for treating infections.
This was the first of what we now call antibiotics—antimicrobial drugs naturally produced by
microorganisms
 Soon after the discovery of penicillin, Selman Waksman isolated a bacterium
from soil, Streptomyces griseus, that produced an antibiotic he called
streptomycin. The realization that bacteria as well as molds could produce
medically useful antimicrobial drugs prompted researchers to begin laboriously
screening hundreds of thousands of different strains of microorganisms for
antibiotic production. Even today, pharmaceutical companies examine soil
samples from around the world for organisms that produce novel antibiotics.
Nobel Prize 1952
FEATURES OF ANTIMICROBIAL DRUGS
Selective toxicity
 Medically useful antimicrobial drugs exhibit selective toxicity, causing greater harm to microorganisms than to the
human host. This is because they target biological structures or biochemical processes that are common in
microorganisms but not human cells. Most antimicrobial drugs, however, can be harmful at high concentrations. The
specific antimicrobial activity and toxicity of a given drug to human (animal) cells is expressed as the therapeutic
index
 Therapeutic index (TI) is a ratio between the amount of
a therapeutic agent that causes the therapeutic effect and
the amount that causes toxicity. In animal studies, TI was
frequently determined as lethal dose of a drug for 50% of the
population (LD50) divided by the minimum effective dose for
50% of the population (ED50). In humans, TI is expressed
as toxic dose 50% divided by minimum effective dose 50%.
 Antimicrobials that have a high therapeutic index are
less toxic to the patient.
 When an antimicrobial that has a low therapeutic index is administered, the concentration in the patient’s
blood must be carefully monitored to ensure it does not reach a toxic level.
FEATURES OF ANTIMICROBIAL DRUGS
Antimicrobial action
 Antimicrobial drugs either kill microorganisms or inhibit their growth, and are, hence, called bactericidal or
bacteriostatic, respectively.
 Bacteriostatic drugs require normal host defenses to kill or
eliminate the pathogen after the suppression of its growth. For
example, treatment of urinary tract infections with sulfa drugs, inhibits
the bacterial growth in the bladder until they are finally eliminated by
the body’s defenses.
 Drugs that kill bacteria are bactericidal. These are particularly
useful in situations in which the normal host defenses are
compromised and cannot remove or destroy pathogens.
 A drug can be bactericidal or bacteriostatic, depending on the concentration of the drug and the growth stage of the
microorganism.
FEATURES OF ANTIMICROBIAL DRUGS
Spectrum of activity
 Antimicrobial drugs vary with respect to the range of microorganisms they kill or inhibit. Those affecting a wide
range of bacteria are called broad-spectrum antimicrobials. These are important in the treatment of acute lifethreatening diseases when immediate antimicrobial therapy is essential and time for pathogen cultivation and
identification is lacking. Their disadvantage is the deleterious effect on normal microbiota.
 Antimicrobials that affect a limited range of bacteria are narrow-spectrum antimicrobials. Their use requires
identification of the pathogen and testing of its susceptibility to antimicrobials, but they cause less disruption to
the normal microbiota.
FEATURES OF ANTIMICROBIAL DRUGS
Tissue distribution, metabolism, and excretion of the drug
 Antimicrobials are differently distributed, metabolized, and excreted by the body. Only some drugs are able to
cross from the blood into the cerebrospinal fluid, which is an important factor for the treatment of meningitis.
Drugs that are unstable at low pH are destroyed by stomach acid when taken orally, and so have to be
administered intravenously or intramuscularly
 Another important characteristic of an antimicrobial is
its rate of elimination, which is expressed as the halflife. The half-life of a drug is the time it takes for the
body to eliminate one-half of the original concentration
in the serum. The half-life of a drug dictates the size
and frequency of doses required to maintain an
effective level in the body.
 Patients who have kidney or liver dysfunction often excrete or metabolize drugs more slowly, and so their
drug dosages must be adjusted.
FEATURES OF ANTIMICROBIAL DRUGS
Adverse effects of antimicrobial drugs
Adverse effects are associated with
allergic reactions,
toxicity to normal tissues and cells, and
suppression of normal microbiota.
Allergic Reactions
Some people develop hypersensitivities or allergies to antimicrobials, which can present as a fever or rash but
can abruptly cause life-threatening anaphylactic shock. Such patients must alert their physicians and pharmacists so
that an alternative drug can be prescribed.
Toxic Effects
Several antimicrobials are toxic to different tissues at high concentrations. Aminoglycosides such as
streptomycin can damage kidneys, impair the sense of balance, and even cause irreversible deafness. For the drugs
with low therapeutic index, treatment of a patient should be carefully monitored. Some antimicrobials have such
severe potential side effects that they are reserved for only life-threatening conditions. Chloramphenicol can rarely
cause the potentially lethal condition aplastic anemia and is used only when no other alternatives are available.
Suppression of normal microbiota
The normal microbiota is important for host defense for its role in excluding pathogens. Antimicrobials change the
composition of the normal microbiota. Patients taking broad-spectrum antibiotics orally sometimes develop the lifethreatening disease called antibiotic-associated pseudomembranous colitis, caused by the growth of toxinproducing strains of Clostridium difficile. This organism normally cannot colonize the intestine due to competition from
other bacteria and only flourishes when those are suppressed by antibiotic.
PHARMACOLOGICAL TARGETS OF ANTIMICROBIAL DRUGS
ANTIBIOTICS TARGETING THE BACTERIAL CELL WALL SYNTHESIS
 The synthesis of bacterial cell walls containing peptidoglycan involves enzymatic pathways specific to the
bacteria and not found in eukaryotes. Hence, the antimicrobial drugs targeting cell wall synthesis do not affect
eukaryotic cells, resulting in a very high therapeutic index.
 Antimicrobial drugs, which target cell wall synthesis, are the beta-lactam drugs (including several classes of
antibiotics) , plus glycopeptide antibiotic, vancomycin, and polypeptide antibiotic, bacitracin.
1.penicillins,
2.cephalosporins,
3.monobactams,
4.carbapenems),
5. vancomycin
6.bacitracin.
 All of them share the structure called a beta-lactam ring and act via the inhibition of a group of enzymes that
catalyze formation of peptide bridges between adjacent glycan strands. These enzymes are commonly called
penicillin-binding proteins (PBPs). The disruption of cell wall leads to an ultimate bacterial cell lysis.
ANTIBIOTICS TARGETING THE BACTERIAL CELL WALL SYNTHESIS

Different beta-lactam drugs vary in their spectrum of activity. Some are more active against Gram(+)
bacteria, whereas others are more active against Gram(-) organisms. Several mechanisms account for these
differences:
1.
Differences in cell wall architecture between Gram(+) organisms, in which peptidoglycan layer directly
contacts the outside environment, and Gram(-) bacteria, in which the outer membrane excludes many
antimicrobials, make the PBP enzymes responsible for cell wall synthesis readily or poorly accessible to
beta-lactams.
The PBPs of different bacterial species have different affinities for a particular beta-lactam drug. PBPs
differ somewhat between Gram(+) and Gram(-) bacteria, as well as between the aerobes and anaerobes, and
even among more closely related organisms.
Some bacteria can resist the effects of certain beta-lactam drugs by synthesizing b-lactamases, the enzymes
that breaks the critical b-lactam ring, destroying the activity of the antibiotic.
2.
3.

Beta-lactamases differ in the range of drugs they destroy. A b-lactamase originally detected in staphylococci
only inactivates the penicillins, hence, it is named a penicillinase. In contrast, the extended-spectrum betalactamases of Gram(-) bacteria inactivate a wide range of beta-lactam drugs including the penicillins and the
cephalosporins.
THE PENICILLINS
 All penicillins share a common basic structure with side chain modifications introduced in the laboratory to
create derivatives with unique characteristics. Currently, the family of penicillins can be loosely grouped into
several categories.
Natural penicillins are the original penicillins produced naturally by the mold
Penicillium chrysogenum. They are narrow-spectrum antibiotics, effective
against Gram(+) and a few Gram(-) bacteria (except the penicillinaseproducing strains. Penicillin V is more stable in acid and, therefore, better
absorbed than penicillin G when taken orally.
Pencillinase-resistant penicillins (methicillin and dicloxicillin) developed against
the penicillinase-producing staphylococci, are modified in their side chain to
prevent penicillinase from inactivating them. Unfortunately, some strains of
penicillinase-producing Staphylococcus aureus synthesize altered PBPs to
which b-lactam drugs, including the penicillins, no longer bind.
Broad-spectrum penicillins (ampicillin and amoxicillin) have a broad spectrum of
activity due to their side chains modifications.They retain their activity against
penicillin-sensitive, Gram(+) bacteria, yet they are also active against Gram(-)
organisms. Unfortunately, they can be inactivated by many b-lactamases.
Extended-spectrum penicillins (ticarcillin and piperacillin) have greater activity
against Pseudomonas species—Gram(-) bacteria resistant to many
antimicrobial drugs, but less activity against Gram(+) organisms. Like the
other broad-spectrum penicillins, they are destroyed by many b-lactamaseproducing organisms.
beta-lactamase inhibitors are chemicals that interfere with the activity of some types
of b-lactamases and protect the co-administered penicillin against enzymatic
destruction. Augmentin® (Amoxiclav) = amoxicillin + clavulanic acid.
THE CEFALOSPORINS
 Cephalosporins include the derivatives of an antibiotic produced by the fungus Acremonium
cephalosporium, as well as the closely related group of antibiotics made by members of a genus of filamentous
bacteria related to Streptomyces.
 Their chemical structure makes them resistant to inactivation by certain b-lactamases, but some have a low
affinity for PBPs of Gram(+) bacteria. The cephalosporins have been chemically modified to produce a family
of various related antibiotics grouped as generation 1 to 5.
Generation 1: cephalexin and cephradine
Generation 2: cefaclor and cefprozil
Generation 3: cefixime and cefibuten
Generation 4: cefepime
Generation 5: ceftaroline
 Also, the third-generation cephalosporins are used for treating diseases of the CNS, while the fourth
generation cephalosporins have improved activity against the gram-negative bacteria involved with urinary
tract infections. Generation 5 drugs are active against the methicillin-resistant Staphilococcus aureus
(MRSA) due to its affinity to PBP2a and against Streptococcus pneumoniae due to its affinity for PBP2x.
CARBAPENEMS AND MONOBACTAMS
 Those two groups of b-lactam drugs are very resistant to b-lactamases. Carbapenems (imipenem and
meropenem) are active against Gram(-), Gram(+), and anaerobes (e.g., Bacteroides fragilis), but not MRSA.
Imipenem is often prescribed in cases where resistances occur, and it appears to have minimal side effects.
It is rapidly destroyed by a kidney enzyme and is therefore administered in combination with an inhibitor,
cilastatin.
 The only monobactam used therapeutically, aztreonam, is primarily effective against members of the family
Enterobacteriaceae. Structurally different from other b-lactam drugs, aztreonam can be given to patients allergic
to penicillin. Interference with platelet function and severe bleeding has limited monobactam use.
OTHER DRUGS TARGETING THE BACTERIAL CELL WALL SYNTHESIS
Vancomycin

Vancomycin is a product of Amycolatopsis (formerly Streptomyces) orientalis, which blocks peptidoglycan
synthesis by binding to the terminal amino acids of the peptide side chain of NAM molecules.

Vancomycin does not cross the outer membrane of Gram(-) bacteria, which are innately resistant, but is an
important medication for treating infections by Gram(+) bacteria resistant to b-lactams (especially severe
staphylococcal diseases). It is sometimes the preferred drug for treating severe cases of antibiotic-associated
colitis. It also is used against Clostridium and Enterococcus species (enterococci), although resistance in
enterococci (responsible for over 10% of all hospital acquired infections in the US) is emerging.

It often is referred to as the “drug of last resort.”
Polymixin and bacitracin – peptide antibiotics

Both bacitracin and polymyxin B are polypeptide antibiotics produced by
Bacillus species. They are quite toxic internally and can cause kidney
damage, and, thus, are restricted to topical use (skin)
 Bacitracin is a cyclic polypeptide that interferes with the transport of cell
wall precursors through the cell membrane. Because it is very toxic taken
internally, bacitracin is only available in ointments for topical treatment of skin
infections caused by gram(+) bacteria or for the prevention of wound
infections.
 Polymyxins are cyclic polypeptides that insert into the cell membrane and
act like detergents, increasing permeability and leading to cell death. They
are most active against gram(-) rods. Polymyxin B is valuable against
Pseudomonas aeruginosa and other gram-negative bacilli causing superficial
MECHANISM OF ACTION OF ANTIBIOTICS TARGETING THE CELL WALL SYNTHESIS
A SUMMARY
Polymixin
Inserts into
the cell
membrane,
increasing
permeability
ANTIBIOTICS TARGETING THE BACTERIAL PROTEIN SYNTHESIS
 The structure of the prokaryotic 70S ribosome (30S+50S
subunits) is different enough from the eukaryotic 80S ribosome
making it a suitable target for selective toxicity.
However, the mitochondria of eukaryotic cells also have 70S
ribosomes, which may partially account for the toxicity of some of
these drugs
1.
2.
3.
4.
Aminoglycosides
Tetracyclines
Macrolides
Chloramphenicol
5. Lincosamides
6. Oxazolidinones
7. Streptogramins
 Chloramphenicol is inhibitiing the rybosomal peptidyl transferase,
a RIBOZYME represented by 23S rRNA localized to 50S subunit.
 Macrolides are also thought to inhibit peptidyl transferase,
in addition to inhibiting ribosomal translocation
(macrolide)
ANTIBIOTICS TARGETING THE BACTERIAL PROTEIN SYNTHESIS
Aminoglycosides (streptomycin, gentamicin, tobramycin, and amikacin).
 In 1943, the first aminoglycoside, streptomycin, was discovered by Selman Waksman and made a sensation for
its activity against M.tuberculosis.

The aminoglycosides irreversibly bind to the 30S
ribosomal subunit, blocking the initiation of translation
and causing misreading of mRNA by ribosomes that have
already passed the initiation step.
 Transport of aminoglycosides into bacterial cells
requires respiratory metabolism, making them inefficient
against anaerobes, enterococci, and streptococci. They are
sometimes used in a synergistic combination with a cell
wall disrupting b-lactam drug, which allows the
aminoglycoside to more easily enter cells
 Severe side effects include hearing loss and kidney
damage. An inhalation form of tobramycin makes
treatment of lung infections in cystic fibrosis patients
caused by Pseudomonas aeruginosa safer and more
effective.
 Recently, they have largely become replaced by secondand third-generation cephalosporins and fluorochinolones.
ANTIBIOTICS TARGETING THE BACTERIAL PROTEIN SYNTHESIS
Tetracyclines (tetracyclin, oxytetracyclin, doxicycline, minocyclin, tigecyclin
In 1948, the first of the tetracycline, chlortetracycline, was discovered. All have the four benzene ring chemical
structure.
 The tetracyclines reversibly bind to the 30S ribosomal subunit, blocking the attachment of tRNA to the
ribosome and preventing the continuation of protein synthesis. The selective toxicity of these bacteriostatic drugs is
due to their active transport into prokaryotic but not animal cells,
Tetracyclines are effective against certain Gram(+) and Gram(-) bacteria and remain
the drugs of choice for most rickettsial and chlamydial diseases and borreliosis.
They are valuable for treating primary atypical pneumonia, syphilis, gonorrhea, and
pneumococcal pneumonia. Tetracyclines such as doxycycline have a longer halflife,
allowing less-frequent doses.
The semisynthetic tetracycline derivatives, glycylcyclines, are effective against some
bacteria resistant against tetracycline. The new drug of this type, tigecycline (Tygacil) is
effective against methicillin-resistant S. aureus (MRSA) infections. Resistance to the
tetracyclines is primarily due to a decrease in their accumulation by the bacterial cell,
either by decreased uptake or increased excretion.
ANTIBIOTICS TARGETING THE BACTERIAL PROTEIN SYNTHESIS
Macrolides (erythromycin, clarithromycin, and azithromycin)
 The macrolides are antibiotics consisting of large carbon rings attached to
unusual carbohydrate molecules, which bind reversibly to the 50S ribosomal
subunit to prevent the chain elongation. The producers of erythromycin are
the soil species Streptomyces erythreus (now called Saccaropolyspora
erythraea) discovered in 1949 by Abelardo Aguilar, a Filipino scientist. Other
macrolides are semi-synthetic drugs with a broader spectrum of activity.
Macrolides act bacteriostatically against a variety of bacteria, including Gram(+) organisms as well as the most
common causes of atypical pneumonia and Legionnaires’ disease and against both Neisseria and Chlamydia
species affecting the eyes of newborns. Members of the family Enterobacteriaceae are resistant to macrolides,
since their outer membrane excludes the drug. Other resistance mechanisms include modification of the ribosomal
RNA target and the production of an enzyme that chemically modifies the drug.
Although macrolides have few side effects, at higher doses it causes nausea, vomiting, and diarrhea.
Chloramphenicol
Chloramphenicol binds to the 50S ribosomal subunit, preventing peptide bonds
from being formed and blocking protein synthesis. Being a broad-spectrum
bacteriostatic drug (Gram(+-), some rickketsia and fungi), it is only used as a last
resort for life-threatening infections in order to avoid a rare but lethal side effect,
aplastic anemia (deficiency in WBC and RBC production). Another side effect is the Gray syndrome occurring in
newborns due to the accumulation of drug in the blood and the lack of glucuronidase activity in them resulting in the
accumulation of toxic products and a sudden breakdown of the cardiovascular system.
 It remains the drug of choice in the treatment of typhoid fever and endemic cholera in some parts of the world,
and is an alternative to tetracycline for epidemic typhus and Rocky Mountain spotted fever.
ANTIBIOTICS TARGETING THE BACTERIAL PROTEIN SYNTHESIS
Linkosamides (lincomycin, clindamycin)
 The lincosamides bind to the 50S ribosomal subunit and prevent protein
chain elongation. Streptomyces lincolnensis produces an antibiotic called
lincomycin from which the semi-synthetic drug clindamycin is derived. Active
against a variety of Gram(-) and Gram(+) bacteria, they are particularly useful for
treating infections resulting from intestinal perforation (peritonitis) because
they inhibit Bacterioides fragilis, a member of the normal intestinal microbiota
frequently resistant to other antimicrobials.
 Unfortunately, the risk of developing antibiotic-associated pseudomembranous colitis is greater for
lincosamides since they are inactive against Clostridium difficile, while eliminating its competitiors, resulting in
accumulation of clostridial toxins.
Streptogramins (quinupristin and dalfopristin)
 Streptogramins are administered together in a medication called Synercid®. They are
the cyclic peptides acting as a synergistic combination, binding to two different sites on
the 50S ribosomal subunit and inhibiting distinct steps of protein synthesis. Individually,
each drug is bacteriostatic but together they are bactericidal. Synercid® is active against a
variety of Gram(+) bacteria including those resistant to b-lactam drugs and vancomycin.
Oxazolidinons (linezolid)
 After the identification of the streptogramins in 1962, no new structural classes of
antibiotics were discovered until the oxazolidinones, in 2000, which interfere with chain
initiation by the 50S subunit. Drugs such as linezolid (Zyvox), are effective in treating
gram(+) bacteria, including MRSA. However, they are drugs of last resort due to
allergic reactions and mitochondrial toxicity
ANTIBIOTICS TARGETING THE NUCLEIC ACID SYNTHESIS
 Several groups of antimicrobial drugs inhibit enzymes required for nucleic acid synthesis, including the
fluoroquinolone and the rifamycin antibiotics, and sulfonamides, which are the antimetabolite drugs.
Fluorochinolones (nalidixid acid, ciprofloxacin, ofloxacin, norfloxacin)
 The synthetic drugs called the fluoroquinolones inhibit one or more of a
group of enzymes called topoisomerases, which maintain the supercoiling of
closed circular DNA, thus, affecting replication and transcription. The
fluoroquinolones are bactericidal against a wide variety of Gram(+-) bacteria.
Acquired resistance is most commonly due to an alteration in the DNA gyrase
target.
Cyprofloxacin
Rifampicins
 Rifampin, a semi-synthetic bactericidal drug derived from Streptomyces
mediterranei, blocks prokaryotic RNA polymerase from initiating
transcription and interferes with RNA synthesis. It is active against
mycobacteria, but prescribed in combination with isoniazid and ethambutol
due to quickly emerging mycobacterial resistance to rifampin. It also is
administered to carriers of Neisseria and Haemophilus species that cause
meningitis as a prophylactic when exposure has occurred.
 In some patients, a reddish-orange pigment appears in urine and tears.
Rifampicin
SULFONAMIDES ARE THE SYNTHETIC DRUGS AFFECTING NUCLEIC ACID SYNTHESIS
 Sulfanilamide is the first of a group of broad spectrum synthetic agents known as sulfonamides or “sulfa drugs”,
which affect bacterial, but not eukaryotic metabolism. Nucleic acid synthesis requires a vitamin called folic acid, which
is synthesized by bacteria, but not humans, who must consume it with food.
 A bacterial enzyme, pteridine synthetase, synthesizes folic acid from
para-aminobenzoic acid (PABA), a molecule structurally similar to
sulfanilamide, pteridine, and glutamic acid. Sulfanilamide competes with
PABA for the active site in the bacterial enzyme leading to inhibition of folic
acid synthesis, which arrests DNA replication.
 Drug resistance is now quite common as mutations have arisen that
allow the microbes to absorb folic acid from outside sources.
 A modern sulfonamide, sulfamethoxazole, is typically combined with
trimethoprim, another synthetic agent that inhibits a next enzymatic step
in folic acid synthesis after the one inhibited by sulfonamides. This
“synergistic” drug, called co-trimoxazole (Bactrim) is effective in much
lower doses than either drug alone and makes the generation of resistance
less likely. The drug is prescribed for urinary tract infections due to gramnegative rods. It is also the primary treatment for Pneumocystis (carinii)
jiroveci pneumonia (PCP) in AIDS patients. They also are used to treat
some kinds of meningitis because they enter cerebrospinal fluid more easily
than do antibiotics.
 Two other important synthetic drugs blocking PABA metabolism in
Mycobacterium species are p-aminosalicylic acid (PAS), which is used for
treating tuberculosis, and dapsone (diaminodiphenylsulfone), which is
effective against leprosy
PRINCIPLE OF ANTIMETABOLITE DRUGS
 Sulfonamides belong to the class of antimetabolite drugs. An antimetabolite is a chemical that inhibits the use
of a metabolite, which is a part of normal metabolism. Such substances are often similar in structure to the
metabolite that they interfere with (for example, sulfonamides and PABA). The presence of antimetabolites can have
toxic effects on cells, such as halting cell growth and cell division.
Antimetabolite drugs include:
1. Base analogs (altered nucleobases);
2. Nucleoside analogs – 2 types, with altered nucleobases and with altered sugar component;
3. Nucleotide analogs;
4. Hydroxyurea;
5. Antifolates.
 The first 3 classes act as antimetabolites, being similar enough to nucleotides to be incorporated into growing DNA
strands; but they act as chain terminators. Hydroxyurea arrests the production of deoxynucleotides by
ribonucleotide reductase. Antifolates inhibit DNA synthesis, since folate is needed to carry one-carbon groups for
methylation reactions and nucleic acid synthesis (the most notable one being thymine, but also purine bases).
OTHER ANTIBACTERIAL DRUGS
 Isoniazid (isonicotinic acid hydrazide, or INH) is an antimetabolite for two vitamins— nicotinamide (niacin) and
pyridoxal (vitamin B6) – which inactivates the enzyme converting the vitamins to useful molecules. Isoniazid must first
be activated by the host catalase, and the destruction of catalase is a mechanism whereby mycobacteria develops
resistance to the drug. The active form of the drug specifically interferes with cell wall synthesis in Mycobacterium
species by inhibiting the production of mycolic acid, an essential component of the mycobacterial cell wall.
 Mycolic
acids
are
important
for
mycobacterial
growth,
survival,
and
pathogenicity. They are found as esters of an
arabinogalactan as well as free lipids in the form
of trehalose dimycolate (TDM). Arabinogalactanmycolate is covalently linked to the cell wall
peptidoglycan via a phosphodiester bond located
on the inner leaflet of the outer membrane. Both
arabinogalactan-mycolate and TDM provide a
protective thick cell wall and protect the TB
bacillus from antibiotics and host's immune
system. TDM also inhibits phago-lysosome
fusion and is considered to be an indicator of
virulent strains.
Since isoniazid-resistant mycobacteria are present in any infection, isoniazid usually is given with another two or
three agents such as rifampin or ethambutol. Ethambutol is a synthetic agent effective against izoniazid-resistant
strains of mycobacteria. Ethambutol is well absorbed and reaches all tissues and body fluids, but resistance occurs.
fairly rapidly, so it is used with other drugs such as isoniazid and rifampin. Its mechanism of action is still unknown.
ANTIFUNGAL MEDICATIONS
 Antifungal agents are being used with greater frequency due to the emergence of resistant strains and greater
numbers of immunocompromised patients (especially, those with AIDS).
Since fungal cells are eukaryotic, similar to the human ones, antifungal drugs are often toxic. At less toxic levels,
many systemic fungal infections are slow to respond. Furthermore, drug susceptibility laboratory tests for
antifungals are lacking. Despite that, numerous effective antifungals are currently available.
Imidazoles and triazoles (clotrimazole, ketoconazole, miconazole, and fluconazole)
 The imidazoles and triazoles comprise a large group of
related synthetic fungicides. They affect fungal plasma
membranes by disrupting the synthesis of membrane
sterols due to the inhibition of fungal cytochrome p450
enzyme “14-a-sterol demethylase”. These agents are used
topically, while ketoconazole was used orally in the past. Some
potentially severe drug interactions may occur, especially with
certain antihistamines and immunosuppressants.
Polyenes (nystatin, amphothericin)
 The polyene family of antifungal agents containing at least two double bonds includes amphothericin and nystatin.
 Amphotericin B derived from Streptomyces nodosus binds to plasma membrane ergosterol (a crystallizing
sterol) found in fungi and some algae and protozoa but not in humans and increases membrane permeability
leading to leakage of glucose, potassium and other nutrients from the cell. The drug is poorly absorbed from the
digestive tract and so is given intravenously. Amphotericin B is the drug of choice in treating most systemic fungal
infections, especially cryptococcosis, coccidioidomycosis, and aspergillosis.
ANTIFUNGAL MEDICATIONS
 Side effects of amphothericin are numerous and sometimes severe. They include abnormal skin sensations,
fever and chills, nausea and vomiting, head ache, depression, kidney damage, anemia, abnormal heart rhythms, and
even blindness.
 NYSTATIN. The polyene antibiotic nystatin (Mycostatin) produced by Streptomyces noursei has the same mode of
action as amphotericin B but is also effective topically in the treatment of Candida yeast infections.
Amphotericin B
Griseofulvin
 Griseofulvin (gris’’e-o-ful’vin) from Penicillium griseofulvum is used
primarily for superficial fungal infections. This fungistatic drug interferes
with fungal growth, probably by impairing the mitotic spindle apparatus
used in cell division.
Although griseofulvin (Fulvicin) is poorly absorbed from the intestinal
tract, it is given orally and appears to reach the target tissues through
perspiration. It is ineffective against bacteria and most systemic fungal
agents but is very useful topically in treating fungal infections of the skin,
hair, and nails. Side effects of griseofulvin are usually limited to mild
headaches but can include gastrointestinal disturbances.
ANTIFUNGAL MEDICATIONS
Flucytosine
 Flucytosine is a synthetic fluorinated pyrimidine transformed in the body to fluorouracil, an
analog of uracil, and thereby interfering with nucleic acid and protein syntheses. It is used in
treating infections caused by Candida and several other fungi. The drug is easily absorbed orally,
but only 10% is converted to an active form, the rest is found unchanged in the urine within 24
hours. Due to lower toxicity and side effects, flucytosine should be given instead of amphotericin B
whenever possible.
Tolnaftate
 Tolnaftate (Tinactin) is a common topical fungicide available
without prescription for the treatment of various skin infections.
Mechanism of action is still not clear.
Terbinafine
 Terbinafine (Lamisil) is a relatively new fungicide approved for topical
use in skin infections and cutaneous candidiasis. Because it is absorbed
directly through the skin, it reaches therapeutic levels in much less time
than do orally administered agents such as griseofulvin.
FEATURES OF ANTIMICROBIAL DRUGS
Resistance to antibiotics
 Resistance to antibiotics can be inherent for certain bacteria and is called innate or intrinsic resistance, as
opposed to the acquired resistance.
 Mycoplasms are resistant to lactam drugs interefering with cell wall synthesis, since they are lacking a cell
wall. Many Gram(-) organisms are intrinsically resistant to certain drugs because the lipid bilayer of their outer
membrane excludes entry of the drug.
Acquried resistance is formed by several mechanisms involving
1.
Drug-inactivating enzymes (penicillinase, chloramphenicol acetyltransferase);
2.
Alteration of pharmacological target molecule (alteration in PBPs prevent beta-lactams from binding, change
of rRNA, the target for macrolides, inhibits their activity);
3.
Decreased uptake of a drug (alterations in porin proteins of Gram(-) bacteria alters the cell wall permeability to
certain drugs);
4.
Increased elimination of a drug (Alterations that result in the increased expression of the efflux pumps that
bacteria use to transport detrimental compounds can increase the overall capacity of a cell to eliminate a drug).
This mechanism can lead to a multidrug resistance.