3rd stage / 2nd course - PowerPoint Presentation

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3rd stage / 2nd course Pharmacognosy III A.Lecturer: Mohammed S. Nawrooz

ANTIBIOTICS

Brief HistoryBefore the discovery of antibiotics, there was nothing much anybody could do.

Streptococcus

pyogenes

caused half of all post-birth deaths and was a major cause of death from burns.

Staphylococcus

aureus

was fatal in 80 percent of infected wounds and the tuberculosis and pneumonia bacteria were famous killers

.

Sir Alexander Fleming’s accidental discovery of the

antibacterial properties

of penicillin in

1929

is largely

credited with

initiating the modern

antibiotic.

By the 1950s, when antibiotics were still new, there was evidence of the emergence of resistance. In fact, within four years of penicillin being introduced to the market, resistant infections were being reported. However, in the 1950s and 1960s, resistant bacterial strains seemed to matter very little. There was always a new antibiotic being developed to combat them

.

Antibiotics

fulfil

a critical infection control function in many areas of medicine including during invasive surgery, in cancer chemotherapy, and in the treatment of elderly or immune-compromised patients.

Discovery ApproachesThe early days of antibiotic discovery were based on fortuitous

(accidental

عرضي

) discoveries of

antimicrobial

activity

(penicillin) or systematic

screens

of soil and fungal

extracts for

bacterial

growth

inhibition. This

first-generation approach

was very successful and resulted in the discovery of most of the major antibiotic classes, discovered through the 1940s and 1950s

.

With the development

of technologies that

allowed rapid bacterial

genome sequencing

, improvements in protein structure determination, and advanced genetic engineering, many pharmaceutical companies initiated a

second-generation approach

to antibiotic drug discovery.

Therefore, a substance is classified as an antibiotic if the following conditions are present:1

. It is a product of metabolism

.

2

. It is a semisynthetic product.

3

.

It is a

synthetic product

produced

as a

structural analog

of a

naturally

occurring antibiotic

.

4

.

It antagonizes the growth or survival of one or more

species of microorganisms

.

5

.they

are in general very effective in helping the body to clear

microbial

infections rapidly

.

6

.they

are relatively safe to use and many can be taken orally

.

7

.

It is effective in low concentrations

.

8

.they

are relatively cheap drugs and thus very widely used.

Very few such compounds have found application in general medical practice, however, because in addition to the ability to combat infections, an antibiotic must possess other

attributes(properties).

First

, it

must exhibit

sufficient

selective

toxicity to be

finally

effective against

pathogenic

microorganisms,

on

the one hand, without causing significant toxic

effects, on

the other.

Second, an antibiotic should be chemically stableenough to be isolated, processed, and stored for a reasonable length of

time without

deterioration of potency. The easy of

an antibiotic

for

oral

or

parenteral

administration to

be

converted

into suitable

dosage forms to provide active drug

in vivo

is

also important

.

Third

,

the rates

of

biotransformation and elimination

of

the antibiotic should be

slow enough

to

allow

a

convenient

dosing schedule, still

rapid

and

complete

enough to facilitate

removal

of the

drug

and its metabolites

from

the body

soon

after administration

has

been discontinued.

COMMERCIAL PRODUCTIONThe commercial production of antibiotics for medicinal

use follows a general pattern, differing in detail for each

antibiotic. The general scheme may be divided into six

steps:

(

a) preparation of

a

pure culture of the desired organism

for use in inoculation of

the

fermentation

medium

;

(b) fermentation, during

which

the

antibiotic

is formed;

(c) isolation

of the

antibiotic

from

the culture medium;

(d) purification;

(

e) assays for potency, sterility, absence of

pyrogens

, and other necessary data; and

(

f)

Formulation into

acceptable and stable dosage forms.

SPECTRUM OF ACTIVITYThe ability of some antibiotics, such as chloramphenicol and the

tetracyclines

, to antagonize the growth of

numerous pathogens

has resulted in their designation as

broad spectrum

antibiotics

. Designations

of

spectrum

of activity are

of somewhat limited

use to

the

physician ,

unless they

are based

on clinical

effectiveness of the antibiotic against specific

microorganisms. Many of the

broad-spectrum antibiotics

are active only in relatively high

concentrations against

some of the species of microorganisms

often included

in the “spectrum.”

Over 30 penicillins have been isolated from fermentationmixtures. Some of these occur naturally; others have been

biosynthesized

by

altering the culture medium to provide

Certain precursors that may

be incorporated

as

acyl groups.

Commercial production of biosynthetic

penicillins

today

depends chiefly

on various strains of

Penicillium

notatum and Penicillium chrysogenum. In recent years, many more penicillins have been prepared semisynthetically and, undoubtedly, many more will be added to the list in attempts to find superior products.

PENCILLINS

Structure of PenicillinsAntibiotics that possess the -lactam (a four-membered cyclic amide) ring structure are the dominant class of agents currently used for the chemotherapy of bacterial infections. The first antibiotic to be used in therapy, penicillin (penicillin G or

benzylpenicillin

), and a close biosynthetic relative,

phenoxymethyl

penicillin (penicillin V), remain the agents of

choice

for the treatment of infections caused by most species of Gram-positive bacteria.

The first step is the condensation of three amino acids—L-α-aminoadipic acid, L-cysteine, L-valine into a tripeptide. Before condensing into the tripeptide, the amino acid L-

valine

must undergo epimerization to become

D-

valine

The condensed

tripeptide

is named

L-

α-

aminoadipyl

-L-cysteine-D-

valine

(ACV). The condensation reaction and epimerization are both catalyzed by the enzyme L-α-aminoadipyl -L-cysteine-D-valine synthetase (ACVS),

The second step in the biosynthesis of penicillin G is the oxidative conversion of linear ACV into the bicyclic intermediate isopenicillin N by isopenicillin N synthase (IPNS),

StereochemistryThe penicillin molecule contains three chiral carbon

atoms (C-2,

C-5, and C-6). All naturally occurring and

microbiologically active

synthetic and semisynthetic

penicillins

have

the same absolute

configuration

about

these three centers.

The carbon

atom bearing the acylamino group (C-6) has the L configuration.