Antibacterial Antibiotics

Paul Anthony P. Balbero RPh.

Part 1
Alexander Fleming: accidentally discovered penicillin in 1929

Antibiotics- are regarded as medical miracles.

Resistance-becomes a problem due to the overuse of these

antibiotics
History:

-Florey and Chain- introduced Penicillin into therapy.

500-600BC- molded curd of soybean weere used in Chinese folklore to treat
carbuncles and boils

1877: Pasteur and Joubert- discovered that anthrax bacilli are killed in the
presence of other microoganisms led to the term antibiosisby Vuillemin
-against life also defined the term survival of the fittest --> literally
means another organism destroying another to preserve its own.

1942: Waksman: proposed the widely cited definition of antibiotics:--> a

substance inhibiting the growth and even of destroying other organisms.
A substance is considered antibiotics if the conditions are met

1. It is a product of metabolism
2. It is a synthetic product produced as a structural analog of a
naturally ocurring antibiotics
3. It antagonizes the growth or survival of one or more species of
microorganisms
4. It is effective in low concentration
Spectrum of Activity

The ability of some antibiotics such as Chloramphenicol and the

tetracyclines to antagonize the growth of certain 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 organisms
Chemoetherapeutic Spectra of Known Antibiotics

Narrow Spectrum
---> Acting only on a single or a limited group of microorganisms
Antibiotics that are effective against Gram (+) organisms and a
selected number of Gram (-) organisms

Broad Spectrum
---> affects wide variety of microorganism species but with a
DISADVANTAGE: it can affect the normal flora and can
precipitate superinfection.
e
Note: Antibiotics that interfere with the metabolic systems found in
microorganisms and not in mammalian cells are the most effective and
successful anti-infective agents.

Ex. 1. Antibiotics which interferes with synthesis of bacterial cell wall have
high potential for selective toxicity.
2. Some antibiotics structuraly resemble some essential metabolites of
microorganisms which suggest that competetive antagonism may be their
mechanism of effects.
3. Many antibiotics interfere with the protein synthesis (Aminoglycosides,
Tetracyclines, Macrolides, Chloramphenicol and Lincomycin
4. Some Antibotics interfere with the nucleic acid synthesis
5. Other antibiotics like polyenes and polymixins are believed to interfere
wih the integrity and function of microbial cell membranes.

Note:
--> The MOA of antibiotic determines in general whether the agents exert a
bactericidal or bacteriostatic activity.
Chemical Classification

The chemisty of antibiotics is so varied that a chemical classification is of

limited value.

Ex. Some important antibiotics have in common a macrolide ring ( a large

lactone ring) ex. are oleandomycin and erythromycin.
Several compounds contain closely related amino sugar moieties such as
those closely related amino sugar moieties such as those in Streptomycin,
Kanamycin, Neomycin, Paromomycin, and gentamicin.
The bacitracins, tyrothricins and polymixins are among a large group of
polypeptides that exhibit antibiotic action
The Penicillins and Beta-lactams ring contain antibiotics derived from amino
acids.
Beta Lactam Antibiotics

Antibiotics that posses the Beta lactam ring (A four-membered

cyclic amide) ring structure are the dominant class of agents
curently used for the chemotherapy of bacterial action.

PenG- BenzylPCN is the first antibiotic to be used in therapy

Pen V Phenoxymethypenicillin
--> both remains a agents of choice for the treatment of
infections caused by most species of Gram-positive bacteria.
Classification of Penicillins

A. Natural Penicillins
--> They have the greatest activity against Gram (+) and Gram (-) cocci and
some anaerobes
---> They are very susceptible to bacterial beta lactamase
Members:
Pen G (IV) , Pen V (PO), Pen G Procaine and Benzathine (IM)

B. Antistaphylococcal Penicillin
--> resistant to beta lactamase enzymes
--> active against Staphylococci and Streptococci
Members: Nafcillin, Isoxazolyl Pencillins, Methicillin
C. AminoPeniciliin
--> Members: Bacampicillin. Amoxicillin, Ampicillin
Cyclacillin

D. Extended Spectrum Penicillin

--> They are susceptible to beta lactamases that is why they are
usually combined with another drug beta lactamase
inhibitors
---> Has improved activity against gram (-) cocci
Members:
2-classes
Carboxypenicillin- Carbenicillin and Ticarcillin
Ureidopenicillin-Mezlocillin and Piperacillin
The discovery of the 2nd mjor group of Beta
lactam drugs, the Cephalosphorins have
provided semisynthetic derivatives that are
effective against bacterial species resistant to
penicillin, particularly penicillinase producing
staphylococci and Gram negative bacilli.
Mechanism of Action of Penicillins

Beta-lactams antibiotics in chemotherapy are very

potent and rapid acting bactericidal against bacteria
in their growth phase and have low frequency of
toxiciy in the host.

Action: Selective Inhibition of the bacterial cell wall

synthesis.
MOA:
---> Inhibition of the biosythesis of dipeptidoglycan that
provides strength and rigidity to the cell wall.
--> Penicillins and cephalosphorins acylate a specific
bacterial D-transpeptidase, thereby rendering the it
inactive for its role in forming peptide cross-links of
two linear peptidoglycan strands by transpeptidation
and loss of D-alanine.
--> D-alanine carboxypeptidase are also inhibited by B-
lactam antibotics.
Penicillin Binding Proteins

--> Binding studies with BenzylPenicillin have

shown that the mechanism of actions of
various beta lactams is much more complex as
it seemed.
--> Studies on the organism E.coli have revealed
as many as seven different functional proteins
(PBPs) have the ff. Functional groups.
Penicillin Binding Proteins

A. PBP 1a and 1b --> transpeptidases involved in peptidoglycan synthesis

associated with cell elongation. Inhibition results to schleroplasts
formation and rapid cell lysis caused by autolysin.
B. PBP2--> transpeptidase involved in maintaining the rod shape of the bacilli.
Inhibition results in ovoid or round forms that undergo delayed lysis.
C. PBP3--> transpeptidase required for septum formation during cell division.
Inhibition results in the formation of filamentous forms containing rod
shaped units that cannot separate.
D. PB4 through 6
--are carboxypeptidases responsible for the hydroysis of D-alanine-D-alanine
terminal peptide bonds of the cross linking peptides. Inhibition of these
enzyme is apparently not lethal to the bacterium even though cleavage of
of the terminal D-alanine bond is required before cross-linkage
The various beta lactam antibiotics differ in
their affinities for PBPs
1. Pen G binds to PBP3
2. First Generation Cephalosphorins bind with
higher affinity to PBP 1a
3. Other general classification of Penicillin binds
to PBP 1, 2, 3
4. Amdinocillin- binds to PBP2
NOMENCTURE OF PENICILLINS
Two numbering system for the fused bicyclic heterocyclic
system occurs:

1. The Chemical Abstracts system initiates the numbering with

the sulfur atom and assigns the nitrogen ring the 4th position
2. The numbering system adopted by the USP is the reverse of
the Chemical Abstract assigning the number 1 to N atom and
4 to the sulfur atom.
Three simpified forms of PCN Nomenclature have been adopted for general
use.

1st: uses the name penam - for the unsubstituted bicyclic system including
the amide carbonyl group.
Thus this naming suggest that PCNs are generally designated acordig to the
Chemical Abstract System as : 5-acylamino-2.2-dimethylpenam-3-
carboxylic acid.

2nd: penicillanic acid - to describe the ring system with substituents that
are generally present (2,2-dimethyl and 3-carboxylic acid
3rd: 6-carbonylaminopenicillanic acid portion of the molecule penicillinand
then distinguishes the compounds accoring to the R-group of the acyl
portion of the molecule.

Ex. Pen G: is BenzylPenicillin

Pen V: PhenoxymethylPCN
Methicillin: 2,6-dimethoxyPCN
Stereochemistry:

The Penicillin molecule contains 3-chiral carbons (C3, C5 and CC6)

--> All of them are naturally occurring and microbiologicaly active synthetic
and semisynthetic penicillins have the same absolute configuration about
these 3 centers
--> the carbon atom bearing the acylamino group (C-6) has the L-
configuration, where as the C where the carboxyl group is attached has
the D configuration
--> the atoms composing the 6-aminopenicillanic acid 6-APA portion of the
structure are derived biosynthetically from 2 amino acids (L-cysteine and
L-valine)
L-cysteine: (S-1, C5, C6, C7 and the 6-amino)
L-valine:( 2,2-dimethyl. C2, C3 and N4 and the 3-carboxyl)
Synthesis of Penicillins
--> examination of the structure of the Penicillin molecule
shows that it possess the beta-lactam-thiazolidine
nucleus
--> isolation of 6-APA from the culture of P. Chrysogenum -
this compound can be converted to PCN by the acylation
of 6-amino group.
-> Sheehan and Ferris- provided another route to synthetic
penicillins by converting a natural penicilln such as Pen
G potassium to an intermediate from the acyl side chain
has been cleaved and which then can be treated to form
biologically active penicillins wih various side chains.
Chemical Degradation of PCN

--> The early commercial penicillin was a yellow to brown amorphous

powder that is very unstable that refrigiration was required to
maintain a reasonable level of activity.
--> All of the natural penicillins are strongly dextrorotatory
--> The solubility and other physicochemical properties of PCN are
affected by the nature of the acyl side chain and by the cations used
to make the salts of the acid.
--> Most penicillins are acids with pka values range from 2.5-3.0.
--> The free acids are not suitable for oral or parenteral administration
--> The sodium and potassium salts are are soluble in water and readily
absorbed orally or parenterally.
--> Salts of Penicillins with organic bases such as benzathine,
procaineand hydrabamine have limited water solubility and are
useful as depot preparations.
The main cause of the deterioration of PCN is the reactivity of
the strained lactam ring particularly to hydrolysis.

--> The course of hydrolysis and the nature of degradation

products are influenced by the pH of the solution. The beta
lactam carbonyl group readily undergoes nucleophilic attack
by water to produce the inactive product penicilloic acid.
--> Other nucleophiles like hydroxylamines, alkylamines and
alcohols open the beta lactam ring to form hydroxamic acids,
amides and esters.
Other agents that inactivates Penicillin
--> Oxidizing agents also inactivates penicillin but reducing agents have
little effects on them.
--> Temperature affects the rate of deterioration ; dry salts are stable at
room temperture and do not require refrigiration
--> prolonged heating inactivates penicillin

Note: Acid catalyzed degradation in the stomach contributes strongly to

the poor oral absorption of penicillin. Thus efforts to obtain penicillins
with improved pharmacokinetic and microbiological properties have
focused on acyl functionalities that would minimize sensitivity of the
beta lactam ring to acid hydrolysis while maintaining antibacterial
activity.