374 METABOLISM OF MICROORGANISMS 



The yield of penicillin has been increased about a thousandfold over 

 that obtained in the beginning of its production. The high yield has 

 been attained largely by selection of better cultures. The best of these 

 have been obtained by treating the mold spores with x-ray, ultraviolet 

 light, or N-mustard gas to give high-yielding mutants. 



Other factors in obtaining high yields have been the use of better 

 media and better methods of aeration and agitation of the media. The 

 improvement in penicillin yields is strikingly similar to the development 

 in wheat-raising. Penicillin production might be called factory farming, 

 for the principles operating are the same as in wheat production. 



Molds produce at least a half dozen different types of penicillin in 

 the same medium. These differ only in the R group part of the mole- 

 mule. Today, only one type of penicillin is wanted in commerce, that 

 is the benzyl or G penicillin, which has the formula 



CeH-CH,-C-NH-CH-C^ C-(CH3)2 



O 0=C N- CH-COOH 



R group Penicillin G 



If a suitable precursor, e.g., phenylacetic acid, is added to the medium, 

 the mold obligingly responds by incorporating this compound into the mol- 

 ecule. Other R groups are: in F penicillin, pentenyl (CH3 • CH2 * CH = 

 CH • CH2-) ; in K penicillin, heptyl (CH3 • CHo • CHo • CHo • CHo • CH2 • 

 CH2 — ). More than 20 penicillins have been obtained by addition of 

 the appropriate precursors. 



Penicillin acts on gram-positive bacteria, and in exceedingly low con- 

 centrations. For example, 0.03 units per milliliter will inhibit the growth 

 of the assay organism Micrococcus pyogenes var. aureus (formerly called 

 Staphylococcus aureus). Since a unit of penicillin is 0.6 /xg., 0.03 unit 

 is less than 0.02 fxg. per milliliter or 2 mg. per 100 1. of medium. A 

 clinical dose of 100,000 units is only 60 mg. Unfortunately, strains of 

 microorganisms that are resistant to penicillin are beginning to appear. 

 These resistant strains probably come from patients who have been re- 

 cently treated with penicillin. 



The most obvious effect of penicillin on the microbial cell is that al- 

 though the cell grows larger, it does not divide. This shows that formation 

 of cell constituents, e.g., proteins and nucleic acids, continues for some 

 time after the penicillin enters the cell. Eventually the enlarged cell 

 bursts. 



Interference with absorption of amino acids, protein synthesis, nucleic 

 acid synthesis, and phosphorylation reactions have all been attributed 

 to penicillin. It is difficult to determine which of these are primary 

 effects and which are secondary manifestations. Metabolism is a series 

 of events, and interference at one place will show up in all subsequent 



