Antibiotics and Antimicrobial Agents

Antibiotics are microbial metabolites or synthetic analogs inspired

by them that, in small doses, inhibit the growth and survival of

microorganisms without serious toxicity to the host. Selective

toxicity is the key concept. Examples are the penicillins and the

tetracyclines.

The first truly effective antimicrobial agents date from the mid

1930s (the sulfonamides) and the first antibiotics came into use in

the 1910s (the penicillins)

In main cases the clinical utility of natural antibi otics has been

enhanced through medicinal chemical ma nipulation of the original

structure leading to broader an timicrobial spectrum, greater

potency, lesser toxicity, more' convenient administration, etc.

Examples of such semisynthetic antibiotics are amoxicillin and

doxycycline.

General principles

Drug Nomenclature

The penicillins are produced by fermentation of fungi and their

names most commonly end in the suffix -cillin as ampicillin.

The cephalosporins are fungal products their names mostly

begin with the prefix cef- or ceph-

The synthetic fluoroquinolones mostly end in the suffix -floxacin.

Antibiotics produced by fermentation of various Streptomyces

species, by convention have names ending with the suffix –

mycin e.g. streptomycin.

Antibiotics produced by fermentation of various

Micromonospora sp. have names ending in -micin e.g.

Gentamicin.

General principles

Broad spectrum antibiotics: they have the potential of inhibiting a

wide range of bacter ial genera belonging to both Gram (+) and

Gram (-) cultures

Narrow-spectrum antibiotics: they inhibit only a few bacterial

genera such as the glycopeptides, typified by vancomycin, which

are used for a few Gram (+) and anaerobic microorganisms.

Bactericidal antibiotics: they will kill bacteria, if the concentration or

the dose is very high.

Bacterostatic antibiotic, will interrupt the growth of the bacteria

and up on withdrawal the growth the organism can resume the

growth and the infection can reestablish it self because it is still

alive.

General principles

The spread between the bactericidal dose and the bacteriostatic

dose is characteristic of a given families e.g.:

With gentamicin, doubling the dose changes the effect on

bacteria from bactericidal to bacteriostatic.

With tetracycline, the difference between the bacteriostatic

and the bactericidal dose is 40 fold.

Synthetic antimicrobial agents

Synthetic antimicrobial agents have not been modeled after any

natural product so they may not properly be called "antibiotics."

Some synthetics are extremely effective for treatment of infections

and are widely used.

They are all effective against key enzymes needed for the

biosynthesis of nucleic acids.

Because they interrupt the biosynthesis of nucleic acids rather than

attacking the finished products or substituting for them in nucleic

acids they are not genotoxic but are comparatively safe to use.

A- Sulfonamides

Sulfonamides were discovered in the mid 1930s following

examination of the Prontosoil rubrum dye.

It was found that; the active substance is p-aminobenzenesulfonic

acid amide (sulfanilamid), formed by reductive liver metabolism of

the administered dye i.e. prontosil rubrum is a pro-drug.

NH2

H2N

NN

SO2NH2

H2N

SO2NH2

Prontosil Rubrum

Liver [H]

Sulfanilamide

Mechanism of Action

Sulfonamides are bacteriosiatic, they inhibit the enzyme

dihydropteroate synthase needed for the biosynthesis of folic acid

derivatives and. ultimately, DNA, How?

They do this by competing at the active site with p-aminobenzoic

acid (PABA) which incorporated into the developing tetrahydrofolic

acid molecule by condensation with a dihydropteroate diphosphate

precursor under the influence of dihydropteroate synthetase.

Mechanism of Action

HN

N NH

N

O

H2N

O P

O

OH

O P

O

OH

OH

Dihydropteroate diphosphate

H2N

COOH

p-Aminobenzoic acidPABA

Dihydropteroate synthase

Sulphonamides

HN

N NH

N

O

H2N

NH

COOH

Dihydropteroic acid

HN

N NH

HN

O

H2N

NH

CONH COOH

COOH

Tetrahydrofolic acid

ThymidineDNA

Biosynthetic action of sulfonamides

+

Mechanism of Action

Thus sulfonamides may be classified as antimetabolites

Most susceptible bacteria are unable to take up preformed folic acid

from their environment and convert it to a tetrahydrofolic acid but,

instead, synthesize their own folates de novo.

As folates are essential intermediates for the preparation of certain

DNA bases, without which bacteria cannot multiply, this inhibition is

strongly bacteriostatic.

Humans are unable to synthesize folates from component parts,

lacking the necessary enzymes (including dihydropteroale

synthase), and folic acid is consumed as a dietary so sulfonamides

have no lethal effect upon human cell growth.

Mechanism of Action

In a few strains of bacteria,

o sulfonamides are attached to the dihydropteroate diphosphate in the place of

the normal PABA giving false metabolite which is not capable of undergoing

condensation with glutamic acid and inhibit the enzyme and the net result is

inability of the bacteria to multiply as soon as the preformed folic acid in their

cells is used up and further nucleic acid biosynthesis becomes impossible.

o Bacteria which are able to take up pre formed folic acid into their cells are

resistant to sulfonamides.

H2N

SO2NH2 Dihydropteroate synthase HN

N NH

N

O

H2N

NH

SO2NH2

Tetrahydrofolic acid

False Metabolite

False Metabolite formation by sulphonamide

Structure-activity Relationships

The strongly electron withdrawing character of the aromaticSO2

group makes the nitrogen atom to which it is directly attached

partially electropositive, thus increasing the acidity of the hydrogen

atoms attached to the nitrogen so that this functional group is

slightly acidic

Replacement of one of the NH2 hydrogen by an electron

withdrawing heteroaromatic ring was not only consistent with

antimicrobial activity but also greatly acidified the remaining

hydrogen and dramatically enhanced potency and dramatically

increases the water solubility under physiologic conditions.

The poor water solubility of the earliest sulfonamides led to

occasional crystallization in the urine (crystalluria) and resulted in

kidney damage because the molecules were unionized at urine pH

values.

Structure-activity Relationships

H2N

SO2NH

O N

Sulfioxazole

CH3

CH3

H2N

SO2N

O N

Sodium Sulfioxazole

CH3

CH3NaOH

Na

HOH+

Therapeutic Applications

H2N

SO2N

O N

Acetylsulfioxazole

CH3

CH3

COCH3

H2N

SO2NH

O N

Sulfioxazole

CH3

CH3

Sulfisoxazole and its pro-drug acetyl sulfisoxazole

Its clinical use is restricted to the treatment of the primary

uncomplicated urinary tract infections.

Sulfisoxazole is well absorbed following oral administra tion

distributes widely and is excreted by the kidneys.

Therapeutic Applications

H2N

SO2N

O N

Acetylsulfioxazole

CH3

CH3

COCH3

H2N

SO2NH

O N

Sulfioxazole

CH3

CH3

Sulfonamides are deactivated by acetylation at N-4 and glucuronation of the aniline nitrogen in the liver.

Allergic reactions are the most common and take the form of rash, photosensitivity and drug fever.

The most severe side effect is the Stevens-Johnson syndrome characterized by sometimes-fatal erythrema multiforme and ulceration of mucous membranes of the eye, mouth and urethra.

Therapeutic Applications

o Other sulfonamides still in use include sulfadiazine, sulfamethizole and sulfamethoxazole.

H2N

SO2NH

S

NN

Sulfamethizole

CH3

H2N

SO2NH ON

Sulfamethoxazole

CH3

H2N

SO2NH

N

N

Sulfadiazine

Therapeutic Applications

o Multiple (or triple) sulfas are a 1:1:1 combination of

sulfabenzamide, sulfacetamide and sulfathiazole which used as a

cream for carderella vaginalis vaginal infection

H2N

SO2NH

S

N

Sulfathiazole

H2N

SO2NH C

O

CH3

Sulfacetamide

H2N

SO2NH C

Sulfabenzamide

O

Therapeutic Applications

o Sulfasalazine is a pro-drug given orally and is largely not absorbed

in the gut so the majority of the dose is delivered to the distal

bowel where reductive metabolism by gut bacteria converts the

drug to sulphapyridine and 5-aminosaliclic acid (Mesalamine).

HO

NN

SO2NH

N

HOOC

H2N

SO2NH

N

HO

NH2HOOC

5-Aminosalicylic acid(Mesalamine)

Sulphapyridine

Gut [H]

Therapeutic Applications

o The liberation mesalamine, an anti-inflammatory agent, is the

purpose for administering this drug. This agent is used to treat

ulcerative colitis and Crohns disease. Direct ad ministration of

salicylates is otherwise irritating to the gastric mucosa.

HO

NN

SO2NH

N

HOOC

H2N

SO2NH

N

HO

NH2HOOC

5-Aminosalicylic acid(Mesalamine)

Sulphapyridine

Gut [H]

N

N

OCH3

OCH3

OCH3

H2N

NH2

Trimethoprim (Proloprim, Trimpex)

Mechanism of Action

Trimethoprim inhibits the dihydrofolate reductase required for

reduction of the exogenous folic acid stepwise to dihydrofolic acid

and then to tetrahydrofolic acid an important cofactor essential for

purine biosynthesis and ultimately for DNA synthesis.

Endogenous produced dihydrofolate must also reduced by the

same enzyme to enter the pathway involved in DNA synthesis.

The bacterial enzyme and the mammalian enzyme both efficiently

catalyze the conver sion of dihydrofolic acid to tetrahydrofolic acid,

but the bacterial enzyme is sensitive to inhibition by trimethoprim

by up to 40,000 times lower concentrations than is the mammalian

enzyme.

This difference explains the useful selective toxicity of trimethoprim

Mechanism of Action

HN

N NH

N

O

H2N

NH

CONH COOH

COOH

Dihydrofolic acid

HN

N NH

HN

O

H2N

NH

CONH COOH

COOH

Tetrahydrofolic acid

TrimethoprimeDihydrofolate reductase

DNA

Dihydropteroic acid

Diaetary folic acid

Site of action of trimethoprime

Dihydrofolate reductase

Therapeutic Application

Trimethoprim is used as a single agent for the oral treatment of

uncomplicated urinary tract infections caused by susceptible

bacteria

Most commonly used in 1:5 fixed ratio with the sulfamethoxazole

(Bactrim, Septra).

This combination is not only synergistic but is less likely to induce

bacterial resistance than either agent alone.

These agents block sequentially at two different steps in the same

essential pathway, and this combination is extremely difficult for a

naive microorganism to survive.

Combined with sulfamethoxazole, it is used for oral treatment of

urinary tract infections, shigellosis, otitis media, traveler's diarrhea,

and bronchitis.

The most frequent side effects of are rush, nausea and vomiting.