Antibiotic Production By Fungi

ANTIBIOTIC PRODUCTION BY FUNGI

Perhaps one of the most important discoveries regarding the beneficial use of fungi for humans was the identification in 1929 by Sir Alexander Fleming that an isolate of Penicillium notatum produced a substance capable of killing Gram-positive bacteria. This compound was subsequently identified as penicillin and was the first member of the βlactam class of antibiotics to be discovered. These compounds function by inhibiting peptidoglycan synthesis in bacteria and their use has reduced the importance of the Gram-positive bacteria as a cause of disease. Subsequent to the identification of penicillin production by P. notatum , a screen revealed that Penicillium chrysogenum was a superior producer. Following a series of mutagenic and selection procedures the strain used in conventional fermentations is capable of producing penicillin at a rate of 7000 mg/L compared to the 3 mg/L of Fleming’s P. notatum isolate. A typical penicillin fermentation yields three types of penicillin, namely F, G and V. The latter can be used directly, however G is modified by the action of penicillin acylase to give a variety of semisynthetic penicillins which show resistance to the action of bacterial penicillinases which are implicated in conferring antibacterial drug resistance.

The majority of antibiotics obtained from fungi are produced by fermentation and most are secondary metabolites, production of which occurs in the stationary phase and is linked to sporulation. Catabolite repression can inhibit antibiotic production and one way to avoid this is to use low levels of glucose in the fermentation medium or to obtain a mutant which is not catabolite repressed. The chemical content of the medium must be monitored since high levels of nitrogen or phosphate (PO ₄) retard antibiotic production. One problem that seriously affects the productivity of antibiotic fermentations is feedback inhibition, where the antibiotic builds to high intracellular levels and retards production or kills the cell. One means of reversing this is to introduce low levels of the antifungal agent amphotericin B, which increases membrane permeability, leading to a decrease in intracellular antibiotic levels and a concomitant increase in production.

Antibiotic production can be maximized by optimizing production as a result of random mutagenesis and selection. Another approach has been to fuse or mate high producing strains with good secretors. Rational selection is a process where a chelating agent is introduced into the fermentation to complex all the metal ions present and consequently has a beneficial effect on antibiotic production. More recently genetic manipulation has been employed to express the genes for antibiotic production in another species which has the possibility of producing hybrid antibiotics with novel targets.