Traditional antibiotics

function by
Traditional targets of
antibacterial compounds
 Inhibiting DNA or
RNA synthesis (for
example,
fluoroquinolones),
 Inhibiting protein
synthesis (for example,
aminoglycosides),
 Inhibiting cell wall
synthesis (for example,
- beta lactams)
 Inhibiting folate
synthesis (for example,
sulfa drugs),
 Depolarizing
membrane potential
(daptomycin).
1930-იან წლებში აღმოჩენილ იქნა,
რომ საღებავი პრონტოზილი
ეფექტურია ჰემოფილური
სტრეპტოკოკით განპირობებული
ინფექციების სამკურნალოდ

 მოგვიანებით დადგენილ იქნა, რომ

პრონტოზილი ორგანიზმში
სულფონამიდად გარდაიქმნება

ყველა სულფონამიდი პარა-

ამინო- ბენზოის (PABA) მჟავას
სინთეზურ სტრუქტურულ
ანალოგს წარმოადგენს

1970-იან წლებში შეიქმნა

სულფონამიდებისა და
ტრიმეტოპრიმის ეფექტური
კომბინაცია
  Paul Ehrlich studied arsenic compounds for their anti-
bacterial properties, and in 1909 invented Salvarsan,
which was applied for the successful treatment of
syphilis.
 This strategy was followed by other researchers to find
active compounds in combating infectious diseases.
 Accordingly, Prontosil, the first sulfa drug, formerly used
as a textile dye, was discovered in 1935, as chemists
searched for an antibacterial drug that might cure the
previously deadly streptococcal infection, a common cause
Paul Ehrlich for chronic pneumonia.
 Its discovery was important enough for German
biochemist Gerhard Domagk to receive the 1939 Nobel
Prize in medicine.
 In 1938, a British research group showed that it was
sulphanilamide that was the actual active antibacterial
agent in Prontosil.
 Many products were later created from this agent,
including sulphapyridine (1938) that was dramatically
successful in reducing the mortality rate of lobar
pneumonia in the 1940s, and saved the life of millions in
military and civil sectors.
Gerhard Damagk  Sulphanilamide only lost its importance with the discovery
of penicillin.
 Today, sulphanilamides are mainly used for reducing
high blood-sugar level and utilized in diuretics.
 Gerhard Damagk spent most of his
adult life in a focused, tireless effort
to find the first cure for a bacterial
infection.
Finally, his laboratory discovered a
sulfa drug they called "Prontosil,"
that seemed effective against strep
and some other infections.
 The drug was prontosil, a dye
which proved to be a pro-drug,
inactive in vitro and needing to be
metabolised in vivo to give the
active product- sulfanilamide.
Damagk published his first
preliminary results on the drug in
February 1935
 An increasing number of doctors
began testing the drug on their
desperate patients.
Gerhard Damagk
 Life is not always unfair:

 In early December 1935, just after the French published the discovery
that pure sulfa was the active ingredient in Prontosil, Domagk's six-
year-old daughter, Hildegarde, suffered a bad accident.
 She was making a Christmas decoration in their house when she
decided that she needed help threading a needle.
 She was on her way downstairs to find her mother, carrying the needle
and thread, when she fell. The needle was driven into her hand blunt
end first, breaking off against a carpal bone.
 She was taken to the local clinic and the needle was surgically
removed, but a few days later, her hand started swelling.
 After the stitches were removed, her temperature rose and kept rising.
 An abscess formed at the surgical site. She had a wound infection.
 The staff at the clinic tried opening and draining the abscess. When it
became reinfected, they opened it again. Then again. The infection
started moving up her arm. "Her general state and the abscess
worsened to such a point that we became seriously concerned,"
Domagk wrote later. "More surgery was impossible." She was falling in
and out of consciousness. The surgeons were talking about
amputating her arm.
 Once the blood tests showed that the invading germ was strep,
Domagk went to his laboratory and pocketed a supply of Prontosil
tablets, returned to her hospital room, put the red tablets in her
mouth himself, and made certain that she swallowed. Then he waited.
 A day later her temperature continued to rise. He gave her more
tablets. No improvement.
 On day three he gave her more, a large dose, but there was still no
improvement. Her situation was growing desperate, so he pulled out
all the stops, on day four giving her more Prontosil tablets, then two
large injections of Prontosil soluble.
 Finally her temperature started to drop. He gave her more tablets.
After a week of treatment, her temperature finally returned to normal.
The infection had been stopped. By Christmas she was able to
celebrate the holidays with her family.
  ტეტრაფოლატსა და მის
ნაწარმებს (რომელთა
კრებითი სახელია
”ფოლატები”) მხოლოდ
მცენარეები და
მიკროორგანიზმები
ასინთეზირებენ.
ფოლის მჟავას სინთეზი  ცხოველები და ადამიანები
ამ კოფაქტორს საკვებთან
ერთად იღებენ
 ფოლატების დეფიციტი
ხშირად ასოცირებულია
ჯანმრთელობის ისეთ
პრობლემებთან,
როგორიცაა ნერვული
ღეროს დეფექტი, ანემიები,
გულის კორონარული
დაავადება, სიმსივნეები
 ანტიმიკრობული
საშუალებებისა და
ჰერბიციდების პოტენციურ
სამიზნეებს ფოლატის
სინთეზში მონაწილე ის
ფერმენტები წარმოადგენენ,
რომელთა ანალოგსაც
ადამიანისა და ცხოველის
ორგანიზმში არ ვხვდებით
  Enzymes requiring folate-derived cofactors are
essential for the synthesis of purines and
Folate Antagonists pyrimidines (precursors of RNA and DNA) and
other compounds necessary for cellular growth
and replication.
 Therefore, in the absence of folate, cells cannot
grow or divide.
 To synthesize the critical folate derivative,
tetrahydrofolic acid, humans must first obtain
preformed folate in the form of folic acid as a vitamin
from the diet.
 In contrast, many bacteria are impermeable to folic
acid and other folates and, therefore, must rely on
their ability to synthesize folate de novo.
 The sulfonamides (sulfa drugs) are a family of anti
bacterials that inhibit this de novo synthesis of folate.
 A second type of folate antagonists
”trimethoprim”prevents microorganisms from
converting dihydrofolic acid to tetrahydrofolic acid,
with minimal effect on a human cell's ability to make
this converThus, both sulfonamides and
trimethoprim interfere with the ability of an
infecting bacterium to divide.
 sion.
 Compounding the sulfonamide sulfamethoxazole
with trimethoprim (the generic name for the
combination is cotrimoxazole) provides a
synergistic combination that is used as effective
treatment of a variety of bacterial infections.
Sulfonamides - Mechanism of action
 In many microorganisms, dihydrofolic acid
is synthesized from p-aminobenzoic acid
(PABA), pteridine, and glutamate .
 All the sulfonamides currently in clinical
use are synthetic analogs of PABA.
 Because of their structural similarity to
PABA, the sulfonamides compete with this
substrate for the bacterial enzyme,
dihydropteroate synthetase.
 They thus inhibit the synthesis of bacterial
dihydrofolic acid and, thereby, the
formation of its essential cofactor forms.
 The action of a sulfonamide is to inhibit
growth of the bacteria, not to kill them,
i.e. it is bacteriostatic rather than
bactericidal.
 The sulfa drugs, including
cotrimoxazole, are bacteriostatic.
Examples of sulfonamides in
clinical use are:
Sulfadiazine
Sulfadimidine
Sulfamethoxazole (short-acting, given
with trimethoprim, the combination
constitutes co-trimoxazole)
Sulfametopyrazine (long-acting)
Sulfasalazine (poorly absorbed in the
gastrointestinal tract)).
MECHANISMS OF ANTIBIOTIC ACTION
 ფოლის მჟავა

 ფოლის მჟავა DNA-ის სინთეზისათვის აუცილებელ პრეკურსორს წარმოადგენს, როგორც

ბაქტერიისათვის, ასევე ადამიანებისათვის
 ფოლის მჟავას სინთეზი მხოლოდ მცენარეებსა და ბაქტერიებში ხორციელდება
 ადამიანის ორგანიზმში ფოლის მჟავას სინთეზი არ მიმდინარეობს , ამიტომ ამ კოფაქტორის
ძირითად წყაროს მწვანე ბოსტნეული წარმოადგენს. უჯრედების მიერ მისი ათვისება
სატრანსპორტო მექანიზმებით ხორციელდება
 ბაქტერიების უმრავლესი სახეობას, აგრეთვე მალარიის გამომწვევი პროტოზოას უსქესო
ფორმებს, არ გააჩნიათ ფოლის მჟავას სატრანსპორტო მექანიზმები, ამიტომ მოკლებულნი
არიან ფოლის მჟავას ათვისების უნარს. ისინი ფოლის მჟავას თვითონ ასინთეზირებენ
 ფოლის მჟავას სინთეზისათვის აუცილებელია p-ამინობენზოის მჟავა (PABA)
 სულფონამიდები სულფონამიდურ ჯგუფს შეიცავენ , რომელიც p-ამინობენზოის მჟავას
(PABA) სტრუქტურულ ანალოგს წარმოადგენს
 Sulfonamides compete with PABA for the enzyme involved in folate synthesis and thus inhibit the
metabolism of the bacteria.
 They are consequently bacteriostatic not bactericidal and are, therefore, only really effective in the
presence of adequate host defences.
 The utilisation of folate, in the form of tetrahydrofolate, as a cofactor in thymidylate synthesis is an
example of a pathway in which there is differential sensitivity of humans and bacterial enzymes to
chemicals.
 This pathway is virtually identical in microorganisms and humans, but one of the key enzymes,
dihydrofolate reductase, which reduces dihydrofolate to tetrahydrofolate, is many times more
sensitive to the folate antagonist trimethoprim in bacteria than in humans.
ფოლის მჟავას ფუნქციები
Folate is present in
dark green
vegetables
It has been found
that folate also
regulates the
production and
synthesis of
serotonine in the
body
Hence one must
consume a lot of
green vegetables to
maintain the
requisite amount
of folate and
serotonine.
  US researchers have revealed the identity of an
enzyme1 used by bacteria to make the essential B
vitamin folate, 30 years after it was first isolated.

The team, led by Mario Amzel and Maurice

Bessman of Johns Hopkins University,
Baltimore, Maryland, say the enzyme could be
a potential target for antibacterial drugs.

When bound to enzymes in the body, each folate

molecule contributes a single carbon atom to the
manufacture of important biological compounds,
including DNA during cell division. 

Although humans cannot synthesise the vitamin,

relying instead on their diet to provide sufficient
folate, bacteria can produce it for themselves.

Image illustrates the stages of enzyme This makes the biochemical synthesis of folate an
activity of the first step of folate biosynthesis: ideal target for antibiotics - knock it out and,
free enzyme (orange), enzyme with
substrate bound (salmon), and enzyme with
hopefully, patients will not suffer too many
pyrophosphate bound (gold), superimposed side effects.
on a drawing of E. coli and the folate
biosynthetic pathway
 The action of sulfonamides and trimethoprim on
bacterial folate synthesis.

Mechanisms. Competes with

PABA, causing inhibition of
dihyropteroate synthase and formation
of non­functional folic acid.
Structures of two representative sulfonamides and trimethoprim . The
structures illustrate the relationship between the sulfonamides and the p-
aminobenzoic acid moiety in folic acid (orange box), and the possible
relationship between the antifolate drugs and the pteridine moiety (orange).
Co-trimoxazole is a mixture of sulfamethoxazole and trimethoprim .
Bridge to Biochemistry
Antimetabolite - A substance inhibiting cell growth by
competing with, or substituting for, a natural substrate in
an enzymatic process.

Suifonamides and trimethoprim are antimetabolites, as

are many antiviral agents and drugs used in cancer
chemotherapy.

Resistance occurs commonly by several mechanisms,

including
 Formation of PABA
 Structural changes in the synthase
 Decreased intracellular accumulation,
 Utilization of folate from exogenous sources.
Sulfonamides - Resistance
 Only organisms that synthesize their
folate requirements de novo are sensitive
to the sulfonamides.
 Thus, humans, who synthesize critical folate
cofactors from dietary folic acid, are not
affected, and bacteria that can obtain
folates from their environment are
naturally resistant to these drugs.
 Acquired bacterial resistance to the sulfa
drugs can arise from plasmid transfers or
random mutations.
 Organisms resistant to one member of
this drug family are resistant to all.
 Resistance is generally irreversible and may be
due to
 An altered dihydropteroate synthetase,
 Decreased cellular permeability to
sulfa drugs
 Enhanced production of the natural
substrate, PABA.
Sulfonamides -Antibacterial spectrum
Sulfa drugs are active
against
Selected enterobacteria in
enterobacteria
the urinary tract
Nocardia
Sulfadiazine, in
combination with the
dihydrofolate reductase
Nocardia
inhibitor pyrimethamine ,
is the preferred form of
treatment for toxoplasmosis
and chloroquine-resistant
malaria.
Toxoplasma gondii
 Sulfonamides - Clinical uses
Combined with trimethoprim (co-
trimoxazole) for Pneumocystis carinii.
Combined with pyrimethamine for drug-
resistant malaria and for toxoplasmosis.
In inflammatory bowel disease and as an
anti-inflammatory drug-sulfasalazine
(sulfapyridine-aminosalicylate combination) is
used.
For infected burns (silver sulfadiazine given
topically).
For some sexually transmitted infections
(e.g. trachoma, chlamydia, chancroid).
For respiratory infections; use now confined
to a few special problems (e.g. infection with
Nocardia).
For acute urinary tract infection (now
seldom used).
 Sulfonamides - Pharmacokinetic aspects
Most sulfonamides are readily absorbed in the
gastrointestinal tract and reach maximum
concentrations in the plasma in 4-6 hours.

Usually not given topically, mainly because of the

risk of sensitisation and allergic reactions.

The drugs pass into inflammatory exudates and

cross the placental and blood-brain barriers.

The drugs metabolised mainly in the liver

 the major product being an acetylated derivative which
lacks antibacterial
Excrated renally as acetylated derivative and
unchanged drug.
 Sulfonamides –Administration:
 After oral administration, most sulfa drugs are well absorbed via
the small intestine
 An exception is sulfasalazine
 It is not absorbed when administered orally or as a suppository
and, therefore, is reserved for treatment of chronic inflammatory
bowel disease (for example, Crohn's disease or ulcerative colitis).
 Local intestinal flora split sulfasalazine into sulfapyridine and 5-
aminosalicylate, with the latter exerting the anti-inflammatory
effect.
 Absorption of the sulfapyridine can lead to toxicity in patients
who are slow acetylators
 Intravenous sulfonamides are generally reserved for patients
who are unable to take oral preparations.
 Because of the risk of sensitization, sulfas are not usually applied
topically.
 However, in burn units, creams of silver sulfadiazine or mafenide
acetate have been effective in reducing burn-associated sepsis,
because they prevent colonization of bacteria.
 Silver sulfadiazine is preferred, because mafenide produces pain on
application.
 Furthermore, mafenide can be absorbed in burn patients, causing an
increased risk of acid-base imbalance.
 Superinfections with resistant bacteria or fungi may still occur.
 Sulfonamides –Distribution:
Sulfa drugs are bound to serum albumin in the
circulation, where the extent of binding depends
on the particular agent's pKa.
In general, the lower the pKa, the greater the
binding.
The drugs pass into inflammatory exudates
Sulfa drugs distribute throughout the body's
water and penetrate well into cerebrospinal
fluid, even in the absence of inflammation.
They can also pass the placental barrier and
enter fetal tissues.
 Sulfonamides –Metabolism and Excretion
Metabolism:
The sulfa drugs are acetylated, primarily in the liver.
 The product is devoid of antimicrobial activity but
retains the toxic potential to precipitate at neutral or
acidic pH.
This causes crystalluria (stone formation) and,
therefore, potential damage to the kidney.
Excretion:
Sulfa drugs are eliminated by glomerular filtration.
Therefore, depressed kidney function causes
accumulation of both the parent compounds and
their metabolites.
The sulfonamides may also be eliminated in breast milk.
Sulfonamides – Adverse Effects
Sulfonamides – Interactions and Contraindications
Drug potentiation
Displacement from binding sites on serum albumin
 Transient potentiation of the hypoglycemic effect of
tolbutamide
 Transient rise in concentration of phenytoin
 Transient potentiation of the anticoagulant effect of
warfarin
 Free methotrexate levels may also rise through
displacement.
Contraindications
 Sulfadrugs should be avoided in newborns and
infants less than 2 months of age as well as in
pregnant women at term due to the danger of
kernicterus.
 Because sulfonamides condense with
formaldehyde, they should not be given to
patients receiving methenamine for UTIs.
Trimethoprim (TMP)- Mechanismm of action
Trimethoprim is an analog of folic
acid that inhibits dihydrofolate
reductase.
 The bacterial reductase has a much
stronger affinity for trimethoprim than
does the mammalian enzyme, which
accounts for the drug's selective toxicity.
 Examples of other drugs that function as
folate reductase inhibitors include
pyrimethamine, which is used with
sulfonamides in treating parasitic infections,
and methotrexate, which is used in the
treatment of cancer, rheumatoid arthritis,
and psoriasis
Resistance, which occurs readily if the
drug is used as a single agent, is via
mutations in the gene that codes for the
reductase.
When used with sulfamethoxazole
(TMP-SMX, cotrimoxazole), there is
synergism and decreased emergence of
resistance resulting from the sequential
blockade of folic acid synthesis
The combination is usually
bactericidal.
Antimicrobial agents that interfere with
the synthesis or action of folate

Sulfonamides are bacteriostatic; they act by

interfering with folate synthesis and thus with
nucleotide synthesis. Unwanted effects include
crystalluria and hypersensitivities.
Trimethoprim is bacteriostatic. It acts by folate
antagonism.
Co-trimoxazole is a mixture of trimethoprim
with sulfamethoxazole , which affects bacterial
nucleotide synthesis at two points.
 Trimethoprim (TMP)
Antibacterial spectrum
The antibacterial spectrum of trimethoprim is similar
to that of sulfamethoxazole.
Trimethoprim is 20- to 50-fold more potent than the
sulfonamide.
Trimethoprim may be used alone in the treatment of
acute UTIs and in the treatment of bacterial
prostatitis (although fluoroquinolones are preferred)
and vaginitis.
Resistance
Resistance in gram-negative bacteria is due to the
presence of an altered dihydrofolate reductase that
has a lower affinity for trimethoprim.
Overproduction of the enzyme may also lead to
resistance, because this can decrease drug permeability.
 Trimethoprim (TMP)
Pharmacokinetics
 The half-life of trimethoprim is similar to that of
sulfamethoxazole.
 Because the drug is a weak base, higher concentrations of
trimethoprim are achieved in the relatively acidic prostatic
and vaginal fluids.
 The drug also penetrates the cerebrospinal fluid.
 Trimethoprim undergoes some O-demethylation, but most of
it is excreted unchanged through the kidney.
Adverse effects
 Trimethoprim can produce the effects of folic acid deficiency.
 Megaloblastic anemia, leukopenia, and granulocytopenia,
especially in pregnant patients and those having very poor diets.
 These blood disorders can be reversed by the simultaneous
administration of folinic acid, which does not enter bacteria.
Clinicai Uses

TMP-SMX has a wide spectrum and many clinical

uses: possible co-DOC in complicated UT
infections and in respiratory, ear, and sinus
infections associated with H. influenzae or M.
catarrhalis; backup drug for I. monocytogenes,
Proteus mirabilis, S. typhi, MRSA, and vibrios.
DOC for prophylaxis and treatment of
Pneumocystis carinii pneumonia.
Pyrimethamine inhibits dihydrofolate reductase
in Toxoplasma gondii and is used with
sulfadiazine in prophylaxis and treatment of
toxoplasmosis.
Clinical uses of
trimethoprim/co-trimoxazole

For urinary tract and respiratory

infections;
trimethoprim , used on its own, is
usually preferred
For infection with Pneumocystis carinii,
which causes pneumonia in patients with
AIDS
Co-trimoxazole is used in high dose.
Adverse Effects
Sulfonamide-related effects are described above,
although crystalluria and drug interactions are
not common with TMP-SMX.
Trimethoprim (and pyrimethamine) may cause
anemia, leukopenia, and thrombocytopenia,
most commonly in debilitated or
immunosuppressed patients.
Hematotoxicity, drug fever, rashes, and
severe GI distress are problematic in patients
with AIDS.
• A variety of drugs used
Pneumonitis to treat other conditions
can cause pneumonitis.
Certain chemotherapy
drugs
 Bleomycin,
methotrexate,
carmustine, busulfan,
cyclophosphamide
Antibiotics
 Nitrofurantoin,
amphotericin B,
minocycline
Sulfonamides
 Sulfasalazine,
sulfadiazine
Nonsteroidal anti-
inflammatory drugs
(NSAIDs)
Amiodarone.
კანის სხვადასხვა სახის რეაქციები

 Morbilliform eruption
(exanthematous drug eruption, maculopapular drug eruption):

 "morbilliform" refers to a resemblance to the rash of measles (morbilli is

Latin for measles); measles is a rare disease now, but morbilliform eruptions
are common
 a morbilliform eruption is symmetrically distributed on the trunk and
proximal extremities, and consists of bright pink macules and slightly raised
papules ("maculopapular")
 Fixed drug eruption
 "fixed" in that it occurs at same sites with each episode
 OTC drugs containing phenolphthalein, pseudoephedrine, etc. common
culprits
 tetracyclines, barbiturates, phenothiazines, sulfonamides
 oval, itchy or burning dusky red plaque
 Erythema multiforme
 a form of cutaneous reaction to an underlying condition. In 50% of cases, a
cause can’t be identified
 common causes: drugs (sulfonamides, phenytoin, barbiturates, penicillin,
etc.); infections (esp. herpes simplex and Mycoplasma); inflammatory bowel
disease
 eruption usually lasts for a week or two, then spontaneously remits
 the "target" lesion is approximately 1cm dull-red macule or papule with a
central area of blistering or hemorrhage
 severe erythema multiforme affecting mucous membranes as well as skin is called
"Stevens-Johnson syndrome"
 Toxic epidermal necrolysis (TEN)
 it is unclear whether TEN is a severe form of erythema multiforme or a distinct disease
 80% of cases have a strong association with a specific drug (list is similar to that for
erythema multiforme)


TEN is a medical emergency, on the order of a total body burn
DNA replication
 DNA replication is a vital function of a living cell. As a cell goes about
its normal functions, DNA must be copied. For an infectious disease
to multiply and spread/infect, the pathogen must be able to replicate
its DNA.Several enzymes are necessary for the process of unzipping
and binding with complementary nucleotides on leading and lagging
strands.
According to Moselio Schaechter, author of Mechanisms of Microbial
Disease, most inhibitors of DNA replication bind to DNA and are too
toxic for clinical use. However, several antibiotics are effective against
DNA synthesis, including metronidazole, nalidixic adic, and other
quinolones. Metronidazoles and nitrofurans are partially reduced
nitro groups that add products to DNA, making it weak and prone to
strand breakage. Some antibiotics, such as nalidixic acid, specifically
bind to enzymes necessary for DNA synthesis. Nalidixic acid and
other quinolones inhibit DNA gyrase, a topoisomerase that uncoils
and coils the DNA.
. A Conventional diagram
used to depict a bacterial
cell and chromosome (e.g.
Escherichia coli).
Note that the E. coli
chromosome is 1300 mm
long and is contained in a
cell envelope of 2 μm × 1
μm; this is approximately
equivalent to a 50 m length
of cotton folded into a
matchbox.
B Chromosome folded
around RNA core, and then
supercoiled by DNA gyrase
(topoisomerase II).
Quinolone and antibacterials
interfere with the action of
this enzyme.
 Fluoroquinolones - Overview
Introduction of the first fluorinated quinolone, norfloxacin, was
rapidly followed by development of other members of this group,
such as ciprofloxacin, which has had wide clinical application.
Newer fluorinated quinolones offer greater potency, a broader
spectrum of antimicrobial activity, greater in vitro efficacy
against resistant organisms, and in some cases, a better safety
profile than older quinolones and other antibiotics.
Compared to ciprofloxacin, the new compounds are more active
against gram-positive organisms, yet retain favor able activity
against gram-negative microorganisms.
It seems likely that the number of drugs in this class of antibiotics
will increase due to its
 Wide antibacterial spectrum
 Favorable pharmacokinetic properties
 Relative lack of adverse reactions.
Unfortunately, their overuse has already led to the emergence of
resistant strains, resulting in limitations to their clinical
usefulness.
Fluoroquinolones - Classification
First Generation
Nalidixic acid
Second Generation
 Norfloxacin
Ciprofloxacin
Ofloxacin
Third Generation
Levofloxacin
Fourth Generation
Moxifloxacin
 Fluoroquinolones - Mechanism of action
 The fluoroquinolones enter the bacterium by passive diffusion through water-
filled protein channels (porins) in the outer membrane.
 Once inside the cell, they inhibit the replication of bacterial DNA by
interfering with the action of DNA gyrase (topoisomerase II) and
topoisomerase IV during bacterial growth and reproduction.
 Topoisomerases are enzymes that change the configuration or topology of
DNA by a nicking, pass-through, and resealing mechanism.
 They do not change the DNA's primary sequence
 Binding of the quinolone to both the enzyme and the DNA forms a ternary
complex that inhibits the resealing step, and can cause cell death by
inducing cleavage of the DNA.
 Because DNA gyrase is a bacteriospecific target for antimicrobial therapy,
cross-resistance with other, more commonly used antimicrobial drugs is rare,
but this is increasing in the case of multidrug-resistant organisms.
 The second site blocked by the fluoroquinolones topoisomerase IV is
required by bacteria for cell division.
 It has been implicated in the process of segregating newly replicated DNA.
 In gram-negative organisms (for example, Escherichia coli), the inhibition
of DNA gyrase is more significant than that of topoisomerase IV,
 In gram-positive organisms (for example, the staphylococci), the opposite is
true - the inhibition of topoisomerase IV is more significant than that of
DNA gyrase
Fluoroquinolones
 The fluoroquinolones include
 The broad-spectrum agents
 Ciprofloxacin, levofloxacin , ofloxacin , norfloxacin , acrosoxacin and
pefloxacin,
 The narrower-spectrum drugs used in urinary tract infections
 cinoxacin , and nalidixic acid (The last named was the first quinolone and is not
fluorinated.)
 These agents inhibit topoisomerase II (a DNA gyrase), the enzyme that produces a
negative supercoil in DNA and thus permits transcription or replication.

Mechanism of action
 The fluoroquinolones are bactericidal analogs of nalidixic acid that interfere with bacterial
DNA synthesis.
 They inhibit
 Topoisomerase II (DNA gyrase), blocking the relaxation of super-coiled DNA,
required for replication,
 Topoisomerase IV, responsible for separation of repli­cated DNA during cell
division.
Resistance is increasing and may occur via
 Increased () drug efflux in the case of P. aeruginosa.
 Changed sensitivity of the target enzymes
 topoisomerase IV in the case of gram-positive cocci (e.g., staphylococci)
 topoisomerase II in the case of E. coli
Mechanism of action
Resistance
Schematic diagram of the action
of DNA gyrase: the site of action
for quinolone antibacterials. A
Conventional diagram used to
depict a bacterial cell and
chromosome (e.g. Escherichia coli).
Note that the E. coli chromosome is
1300 mm long and is contained in a
cell envelope of 2 μm × 1 μm; this is
approximately equivalent to a 50 m
length of cotton folded into a
matchbox. B Chromosome folded
around RNA core, and then
supercoiled by DNA gyrase
(topoisomerase II). Quinolone and
antibacterials interfere with the
action of this enzyme.
Activity and Clinical Uses
Wide spectrum
 Gram-positive cocci
 Gram-negative cocci

 Many gram-negative rods {E. coli, S. typhi, Shigella,

Serratia marcescens, etc.)
 Some anaerobes (C. jejuni)

 Mycobacteria (e.g., multi-drug-resistant M.

tuberculosis).
Active when administered orally (inhibited by
antacids) and have a wide tissue distribution,
including bone.
Antimicrobial agents affecting DNA
topoisomerase II
These drugs-the fluoroquinolones, e.g.
ciprofloxacin-interfere with the supercoiling of DNA.
Ciprofloxacin has a wide antibacterial spectrum,
being especially active against Gram-negative
enteric coliform organisms including many
organisms resistant to penicillins, cephalosporins
and aminoglycosides; it is also effective against
Haemophilus influenzae, penicillinase-
producing Neisseria gonorrhoeae,
Campylobacter sp. and pseudomonads. There is a
high incidence of staphylococcal resistance. It is
active orally with a half life of 4.5 hours.
Unwanted effects include gastrointestinal tract
upsets, hypersensitivity reactions and, rarely,
CNS disturbances.
Drugs
Drug group includes norfloxacin (UT only),
ciprofloxacin, and multiple other
fluoroquinolones (FQs).
FQs may have enhanced activity against
resistant pneumococci (sparfloxacin) and
Chlamydia (ofloxacin).
Ciprofloxacin has been used widely in
respiratory, GI, UT, urogenital, and other
soft tissue infections.
Ciprofloxacin and ofloxacin are alternative
drugs for gonorrhea (single doses).
Pharmacokinetic aspects
 Given orally, the fluoroquinolones are well absorbed.
 Aluminium and magnesium antacids interfere with the absorption
of the quinolones.
 The half-life of
 Ciprofloxacin and norfloxacin is 3 hours,
 Ofloxacin is 5 hours
 Perfloxacin is 10 hours.
 The drugs concentrate in many tissues, particularly in the kidney,
prostate and lung.
 All quinolones are concentrated in phagocytes.
 Most do not cross the blood-brain barrier except for pefloxacin and
ofloxacin, which reach, in the CSF, 40% and 90%, respectively, of their
serum concentrations.
 Elimination of
 Ciprofloxacin, norfloxacin and enofloxacin
 partly by hepatic metabolism by P450 enzymes (which they can inhibit, giving
rise to interactions with other drugs)
 partly by renal excretion. ‘
 Pefloxacin is metabolised to norfloxacin .
 Ofloxacin is excreted in the urine.
Clinical uses of the fluoroquinolones
Complicated urinary tract infections
(norfloxacin, ofloxacin)
Pseudomonas aeruginosa
Respiratory infections in patients with cystic
fibrosis
Invasive external otitis

Chronic Gram-negative bacillary osteomyelitis

Eradication of Salmonella typhi in carriers
Gonorrhoea (norfloxacin, ofloxacin)
Bacterial prostatitis (norfloxacin)
Cervicitis (ofloxacin)
Anthrax.
Adverse Effects
 GI distress
 Most common side-effects are nausea , vomitting and diarrhoea ,
with an occurrence rate ranging from 3 to 17 percent
 Rash, phototoxicity (especially sparfloxacin).
 CNS effects usually mild (insomnia, dizziness, and headache)
 Effects such as insomnia , dizziness and anxiety have been reported in
0.9 to 11 percent patients .
 Seizures are a rare occurrence but have been increasingly reported in
overdose, or when used with Theophylline or with NSAID's .
 Crystaluria - Associated with fluoroquinolones except Levofloxacin ,
Gatifloxacin, Moxifloxacin, and Trovafloxacin . Patients are instructed to
drink plenty of water.
 Liver Toxicity -  In 18 months post-approval follow up by US Food and
Drug Administration  (FDA)  for Trovafloxacin 140 cases of liver toxicity
were found .
 Phototoxicity - Most likely to occur with the use of Ciprofloxacin,
Lomefloxacin, Norfloxacin.
 Achilles Tendonitis- Both older and newer fluoroquinolones have been
shown to be associated with arthropathy in weight bearing joints .
Studies have shown erosion and permanent lesions of cartilage due to
quinolone use in animals .
Contraindication and Drug-specific toxicity
Drug-specific toxicity:
Cardiac - QT prolongation is thought to be
due to halogen substitution at the number 8
position ( e.g Moxifloxacin, sparfloxacin)
Hepatotoxicity (trovafloxacin).
Tendonitis (and tendon rupture) has occurred
in adults.

Contraindication :
Pregnancy
Children
based on animal studies showing effects on
collagen metabolism and cartilage
development;
 Sites of anaerobic infections
Metronidazole

Mechanism of Action
 Mechanism of antibacterial action is unclear, but it appears to necessitate
reductive metabolism of the drug—bactericidal.
Metronidazole
Clinical Uses
Antiprotozoal
 Metronidazole is DOC for most infections caused by
 Entamoeba histolytica
 Giardia species

 Trichomonas vaginalis.

Antibacterial
 DOC for most anaerobic infections including those caused by
 B. fragilis
 C. difficile
 G. vaginalis
 H. pylori-associated GI ulcers.
Adverse Effects
Metallic taste
Brown-black urine
Glossitis, stomatitis
Urethral burning, dysuria
Neurotoxicity (vertigo, peripheral neuropathy).
Disulfiram-like interactions with ethanol.
 Metronidazole
 Pharmacokinetics
 Metronidazole and tinidazole are effective orally and are distributed
widely to tissues, achieving cerebrospinal fluid (CSF) levels
similar to those in the blood.
 Metronidazole can also be given intravenously
 Metronidazole is available in topical formulations.
 Elimination of the drugs require hepatic metabolism, and dosage
reduction may be needed in patients with liver dysfunction.
 Tinidazole has a long elimination half-life permitting once-daily
dosing.
 Toxicity
 Adverse effects include
 Gastrointestinal irritation, headache, and dark coloration of
urine.
 More serious toxicity includes leukopenia, dizziness, and ataxia.
 Opportunistic fungal infections may occur during treatment with
metronidazole and tinidazole.
 Drug interactions with metronidazole
 disulfiram-like reaction with ethanol
 potentiation of coumarin anticoagulant effects.
 Although metronidazole and tinidazole are not contraindicated in
pregnancy, the drugs should be used with caution.