176 Perspectives in Microbiology 



antibiotic. The sometimes striking antagonistic and syner- 

 gistic effects when antibiotics are used in combination are 

 of obvious central importance in relation to their thera- 

 peutic use, but the factors underlying those effects are 

 almost wholly obscure. 



Many of the reported metabolic effects of antibiotics are 

 observed with whole-cell suspensions, in which it is no- 

 toriously difficult to distinguish between a primary locus 

 of action of the antibiotic and metabolic effects resulting 

 from that combination which may, however, be two, three, 

 or more steps removed. Uncommon interest therefore at- 

 taches to the recent demonstration by Saz that in a cell- 

 free bacterial extract, chlortetracycline in minute concen- 

 tration inhibits an aryl nitro-reductase of Escherichia coli. 

 This inhibition apparently results from the fact that the 

 antibiotic combines with Mn, which is an essential cofactor 

 in one or more of the multiple enzyme systems involved in 

 this complex reaction. Interesting also is the fact that oxy- 

 tetracycline, although it also chelates with Mn, is far less 

 inhibitory than is chlortetracycline. Whether or not this 

 is the mechanism by which chlortetracycline exerts its 

 growth-inhibitory effect on bacteria, it is the first clear 

 demonstration of a direct effect of an antibiotic on an 

 enzyme system in a cell-free bacterial extract and, as such, 

 may prove a model for the actual mode of action of this 

 and other antibiotics. 



Our ignorance extends not only to the mode of action 

 of antibiotics at the cellular level, but indeed to how they 

 work in vivo, for some of the antibiotics, notably chlor- 

 amphenicol and the three tetracyclines, are effective thera- 

 peutically at concentrations in the body fluids which are 

 only growth inhibitory in vitro. The therapeutic response 

 clearly involves the participation of host mechanisms to 

 an important degree; but whether we are here dealing 

 with a humoral or a cellular effect has not yet been 

 clarified. 



