DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1478 was that of a policeman who was suffering from a severe mixed
staphylococcal and streptococcal infection. He was treated with penicillin,
some of which had been recovered from the urine of other
patients who had been given the drug. It is said that an Oxford professor
referred to penicillin as a remarkable substance grown in bedpans
and purified by passage through the Oxford Police Force.
A vast research program soon was initiated in the U.S. During
1942, 122 million units of penicillin were made available, and the
first clinical trials were conducted at Yale University and the Mayo
Clinic, with dramatic results. By the spring of 1943, 200 patients
had been treated with the drug. The results were so impressive that
the surgeon general of the U.S. Army authorized a trial of the antibiotic
in a military hospital. Soon thereafter, penicillin was adopted
throughout the medical services of the U.S. Armed Forces.
The deep-fermentation procedure for the biosynthesis of
penicillin marked a crucial advance in the large-scale production of
the antibiotic. From a total production of a few hundred million units
a month in the early days, the quantity manufactured rose to over
200 trillion units (nearly 150 tons) by 1950. The first marketable
penicillin cost several dollars per 100,000 units; today, the same dose
costs only a few cents.
Chemistry. The basic structure of the penicillins, as shown in Figure
53–1, consists of a thiazolidine ring (A) connected to a β-lactam ring
(B) to which is attached a side chain (R). The penicillin nucleus itself
is the chief structural requirement for biological activity; metabolic
transformation or chemical alteration of this portion of the molecule
causes loss of all significant antibacterial activity. The side chain
(Table 53–1) determines many of the antibacterial and pharmacological
characteristics of a particular type of penicillin. Several natural
penicillins can be produced depending on the chemical
composition of the fermentation medium used to culture Penicillium.
Penicillin G (benzylpenicillin) has the greatest antimicrobial activity
of these and is the only natural penicillin used clinically. For penicillin
G, the side chain (R in Figure 53–1) is a phenyl-methyl
substituent (Table 53–1).
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Semisynthetic Penicillins. The discovery that 6-aminopenicillanic acid
could be obtained from cultures of P. chrysogenum that were depleted
of side-chain precursors led to the development of the semisynthetic
penicillins. Side chains can be added that alter the susceptibility of the
resulting compounds to inactivating enzymes (β-lactamases) and that
change the antibacterial activity and the pharmacological properties
of the drug. 6-Aminopenicillanic acid is now produced in large quantities
with the aid of an amidase from P. chrysogenum (Figure 53–1).
This enzyme splits the peptide linkage by which the side chain of
penicillin is joined to 6-aminopenicillanic acid. Table 53–1 shows the
variety of side chains that have been added to 6-aminopenicillanic
acid to produce the medicinal penicillins in current use; the table also
summarizes their major therapeutic properties (e.g., absorption following
oral administration, resistance to penicillinase, and antimicrobial
spectrum).
Unitage of Penicillin. The international unit of penicillin is the specific
penicillin activity contained in 0.6 μg of the crystalline sodium
salt of penicillin G. One milligram of pure penicillin G sodium thus
equals 1667 units; 1.0 mg of pure penicillin G potassium represents
1595 units. The dosage and the antibacterial potency of the semisynthetic
penicillins are expressed in terms of weight.
Mechanism of Action of the Penicillins and Cephalosporins. The
β-lactam antibiotics can kill susceptible bacteria. Although knowledge
of the mechanism of this action is incomplete, numerous
researchers have supplied information that allows understanding of
the basic phenomenon (Bayles, 2000; Ghuysen, 1991).
The cell walls of bacteria are essential for their normal growth
and development. Peptidoglycan is a heteropolymeric component of
the cell wall that provides rigid mechanical stability by virtue of its
highly cross-linked latticework structure (Figure 53–2). In grampositive
microorganisms, the cell wall is 50-100 molecules thick,
but it is only 1 or 2 molecules thick in gram-negative bacteria (Figure
53–3A). The peptidoglycan is composed of glycan chains, which are
linear strands of two alternating amino sugars (N-acetylglucosamine
and N-acetylmuramic acid) that are cross-linked by peptide chains.
The biosynthesis of the peptidoglycan involves ~30 bacterial
enzymes and may be considered in three stages. The first stage,
precursor formation, takes place in the cytoplasm. The product, uridine
O
S CH 3
R C NH CH CH C
B A CH
2
3
O C N CH COOH
Penicillins
1
1
2
A
B
Site of action of penicillinase
Site of action of amidase
Thiazoline ring
-lactam ring
Amidase
Penicillinase
O
S CH 3
O
S CH 3
R CH NH 2 CH CH C
R C NH CH CH C
CH 3
CH 3
O C N CH COOH
O C N CH COOH
O
OH H
R
CH
6-Aminopenicillanic acid
Penicilloic acids
Figure 53–1. Structure of penicillins and products of their enzymatic hydrolysis.