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Terbinafine

Like griseofulvin, terbinafine (Fig. 17.11) can be taken

orally (or topically) and it tends to accumulate in the

skin, nails, hair, and fatty tissues. It inhibits ergosterol

synthesis by interfering with an early step in sterol

biosynthesis, where the enzyme squalene epoxidase

starts the process of cyclization leading to lanosterol.

Polyene macrolide antibiotics

The polyene macrolide antibiotics are produced by

several Streptomyces spp. Their typical structure is

exemplified by amphotericin B (Fig. 17.12). An

aminosugar group is attached to a large lactone ring

with a series of double bonds on one face (hence the

term polyene) and a series of hydroxyl groups on the

other face. So the molecule has both a hydrophobic

and a hydrophilic face. By X-ray crystallography the

molecule is seen to have a rod-like structure, about

2.1 nm long in the case of amphotericin B, similar to

a membrane phospholipid. The polyenes insert in the

cell membrane by associating with sterols (the hydro-

phobic face) and are thought to cause rearrangement

of the sterols so that a group of eight polyene molecules

forms a ring with the hydrophilic faces in the center

(Fig. 17.13). Thus they form a polar pore through

which small ions (K+, H+) can pass freely, disrupting

the cell’s ionic control.

Almost all eukaryotic cells have sterols in the mem-

branes, although some Oomycota do not produce

them or even need them for growth. So the polyene

antibiotics would not, at first sight, seem to be select-

ive antifungal agents. However, there are many different

polyenes that differ in the ring size and presence

or nature of the aminosugar group, and they show

preferential binding to different sterols. Three of these

compounds – amphotericin B, nystatin, and pimaricin

• have a much higher affinity for ergosterol than for
  cholesterol, the mammalian membrane sterol, so they
  are selectively antifungal. Nystatin and pimaricin can be
  applied topically as creams to control Candidainfection
  of the vagina, or as powder formulations to control
  athlete’s foot.
  Amphotericin B has lower mammalian toxicity than
  nystatin or pimaricin, and it also has some (low)
  degree of water solubility. Initial development work
  in the 1950s and 1960s showed that amphotericin B
  could be administered orally, with some success. But
  all the polyene antibiotics have adverse side effects,

PRINCIPLES AND PRACTICE OF CONTROLLING FUNGAL GROWTH 351

CH 3

CH 3

H 3 C

HO

CH 3

H 2 N

OH

OH

OH

OH

COOH

O OH OH OH OH O OH

O

O

O

Fig. 17.12Amphotericin B, a member of the polyene macrolide class of antifungal antibiotics.

Fig. 17.13Proposed mode of action of

amphotericin B and similar large polyene

antibiotics. The antibiotic shows strong

affinity for ergosterol in the fungal

cell membrane. It binds to ergosterol

molecules and repositions them so that

the polyene–sterol complexes assemble

to form a polar pore through which

small ions diffuse freely. Note that only

one layer of the phospholipid bilayer is

shown in this diagram. (Based on a dia-

gram in Gale et al. 1981.)