Antibiotics - Drug Design and Discovery - page 431

OH

HC O

(CH 2 ) 2

AZI-Gly- L -Ala- D -Leu- L -Ala- D -Val- L -Val- D -Val- L -Tr y- D -Leu-AzII- D -Leu- L -Tr y- D -Leu- L -Tr y-NH

AZI

AZII

L -Val
L -Val

L -Tr y
L -Phe

Valine gramicidin A
" "

L -Ileu
L -Ileu

L -Tr y
L -Phe

Isoleucine gramicidin A
" "

HCl

D -Phe

L -Val L -Orn L -Leu L -Pro

L -Tyr Glu L -Asp

Z Y

NH 2 NH 2

Y Z

Tyrocidine A:
Tyrocidine B:

D -Phe
L -Tr y

D -Phe
D -Phe

FIGURE 25.4 Tyrothricin components.

25.3.1.2 Polymyxin
Polymyxin was discovered in 1947 almost simultaneously in three different laboratories in the
United States and England. It has been shown that Bacillus polymyxa and B. aerosporus were
identical species and an agreement was reached on one name: polymyxin. Several polymyxins A,
B, C, D, and E were isolated, but polymyxin B, which seemed to be the least toxic, was introduced
in medicine. A peptide antibiotic, colistin, isolated in 1950 in Japan from B. colistinus was shown
to be identical with polymyxin E. Both polymyxin B and E contain several components differing
in the structure of the fatty acid. The most important component is B 1 (or E 1 ), with some 15%-25%
of B 2 (or E 2 ). Polymyxin and colistin have i ve free amino groups and are used as the sulfate salt.
A sulfomethyl derivative, obtained by reaction with formaldehyde and bisulphite, and which is less
toxic, is used for injection. These peptides have been used for the treatment of infections by Gram-
negative bacteria like Pseudomonas , but this treatment is seldom used now, because less toxic anti-
biotics are available. Because these peptides are neurotoxic and nephrotoxic, their use is limited
usually to ear- and nose-drops, and treatment of skin infections (Figure 25.5).

25.3.2 A NTIBIOTICS WITH A LTERED M EMBRANE P ERMEABILITY

25.3.2.1 Gramicidins
Their structure is given in Figure 25.4.

25.3.2.2 Polyether Antibiotics
An important group of antibiotics with a polyether structure has been described. These antibiotics
have a certain activity against Gram-positive bacteria but their main application lies in the treatment
of coccidiosis. Monensin, which was isolated in 1967 from Streptomyces cinnamonensis , is used as
coccidiostat in poultry and as growth promoter in ruminants (cattle and sheep). Other polyethers are
lasalocid, salinomycin, and nigericin (Figure 25.6).