MODES OF ACTION OF ANTIBIOTICS 



97 



cyclines, erythromycin, and puromyciu ex- 

 plains the above additive effect. 



According to Korotajev (1959), chloram- 

 phenicol does not influence the aerobic oxi- 

 dation of pyruvic acid by resting cells of 

 E. coli but inhibits anaerobic pyruvate 

 metabolism. Pyruvate consumption by rest- 

 ing cells oi Shigella flexneri is inhibited under 

 aerobic conditions and under conditions of 

 limited oxygen supply. Schneierson et al. 

 (1960) emphasized that chloramphenicol, in 

 concentrations that fail to inhibit growth, is 

 capable of depressing pigment synthesis by 

 Pseudomonas aeruginosa. The antibiotic 

 exerts its action by interfering with biosyn- 

 thesis of the pigment by the organism, no 

 reducing effect upon pigment already formed 

 being demonstrated. A single exposure to 

 chloramphenicol resulted in a complete and 

 permanent loss of the ability to produce the 

 pigment in three of the four strains tested. 



Tetracyclines 



It is generally assumed that chlortetra- 

 cycline, oxytetracycline, and tetracycline, 

 because of their close chemical i-elation- 

 ship, have similar, if not identical, modes of 

 action (Hahn, 1958). Tetracycline is the 

 parent compound, chlortetracycline has a 

 chlorine atom in the unsaturated (D) ring, 

 and oxytetracycline instead of a hydrogen 

 has a hydroxyl group in the B ring. The 

 antibiotic spectra of all three are similar 

 (Love et al., 1954), and mutual cross-resist- 

 ance has been found (Wright and I'^inland, 

 1954). There are, however, reports of ([uali- 

 tative as well as (luantitative differences in 

 their inhil)itory effects, and therefore the 

 possibility must be entertained that differ- 

 ences exist in their modes of action. Ciuil- 

 laume and Osteux (1959) have shown that 

 chlortetracycline inhibits two different enzy- 

 matic systems in Proteus mirahilis, that ot" 

 oxidation of glucose, pyruvic acid, and ace- 

 tate, and that of the citric acid cycle. 



The tetracyclines affect oxidation and fer- 



mentation in susceptible bacteria; inhibi- 

 tion of protein synthesis has been reported; 

 and finally, by virtue of the strong chelating 

 properties of all three antibiotics, interfer- 

 ence with \-arious cellular and enzymatic 

 processes has been suggested as a possible 

 mechanism of inhibition. 



The inhibitory activities of the tetracy- 

 clines on various oxidative properties of 

 whole bacteria have been noted. In the in- 

 terpretation of these data, the difficulty of 

 distinguishing between primary action and 

 secondary effects on dead or dying cells 

 must again be considered. For example, it 

 has been reported (McCullough and Beal, 

 1952) that chlortetracycline at concentra- 

 tions of 250 to 500 ng per ml inhibits oxida- 

 tion of glucose, pyruvate, fructose, xylose, 

 and trehalose by Brucella (Fig. 6). Oxidation 

 of tricarboxylic acid cycle intermediates by 

 E. coli, Ps. aeruginosa, and Pr. vulgaris was 

 similarly inhibited by high concentrations 

 of chlortetracycline. Oxytetracycline in 

 analogous concentrations was also found to 

 inhibit these oxidations (Wong et al., 1953). 



The tetracyclines were also found to cause 

 serious derangement of cellular processes 

 leading to protein synthesis and nucleic acid 

 formation. 



According to Bernheim and De Turk 

 (1952), chloramphenicol, streptomycin, and 

 the tetracyclines inhibit the oxidation and 

 to a lesser extent the deamination of phen- 

 ylalanine, tyrosine, and phenylserine by a 

 strain of Ps. aeruginosa. They also inhi})it 

 the oxidation of succinate and certain other 

 dicarboxylic acids. It was suggested that 

 these antibiotics interfere with the formation 

 of compounds which may be necessary for 

 the assimilation of ammonia or, in the case 

 of phenylalanine, for its oxidation. Bern- 

 heim (1954) has further shown that Ps. 

 aeruginosa on contact with succinate pro- 

 duces a cell constituent which can be utilized 

 for the synthesis of an enzyme that oxidizes 

 benzoic acid. The above antibiotics inhibit 



