Forbes , M. (Lederle Laboratories Division, Pearl River, N.Y.), N. A. Kuck, and E. A. Peets . Mode of action of ethambutol. J. Bacteriol. 84: 1099–1103. 1962.—Ethambutol [2,2′-(ethylenediimino) di-1-butanol] arrested multiplication of Mycobacterium smegmatis cells and eventually effected their death. The inhibitory effect of the drug on multiplication did not become apparent until several hours after its addition to the culture. The drug had no effect on the survival of nonproliferating cells. It had little or no effect on the metabolism of nonproliferating cells, but cells from cultures whose growth had been inhibited by ethambutol showed evidence of impaired metabolism. C 14 -labeled ethambutol was taken up rapidly by both proliferating and nonproliferating cells. The observations are consistent with the hypothesis that ethambutol exerts its antibacterial effect by interfering with the synthesis of a metabolite(s) needed for multiplication. Depletion of the metabolite(s) results in arrest of multiplication, impairment of metabolism, and loss of viability. Resistance to ethambutol cannot be explained by the failure of the cells to take up the drug, since the drug was equally bound by resistant and sensitive cells.

Minocycline was the most active of six antibiotics tested against 65 clinical isolates of Acinetobacter calcoaceticus (syn.: Herellea, Mima) received from six medical centers. In the Bauer-Kirby disk susceptibility test, all isolates were rated susceptible to minocycline, gentamicin, and polymyxin; 25% were resistant to tetracycline. In agar dilution tests, minocycline was two to four times more potent than gentamicin or polymyxin and eight times more potent than tetracycline. Ampicillin and cephalexin were relatively ineffective. Against lethal infections produced by five strains ofA. calcoaceticus in mice, minocycline was, in general, more active than gentamicin or polymyxin on a dosage basis and significantly more active on a blood-level basis. Minocycline was significantly more potent than tetracycline on both dosage and blood-level bases against tetracycline-sensitive and -resistant strains. In the last decade there has been an increase in the reported incidence of acinetobacters in a variety of infections. The cultures are susceptible to few antibiotics. Our data show that minocycline could offer an effective alternative to the more toxic drugs for the treatment of these infections. Susceptibility should be determined with minocycline disks.Acinetobacter strains have been assuming significance in clinical infections. Appearing throughout scientific reports under many synonyms (Herellea, Mima, Bacterium anitratum), these ubiquitous organisms were originally considered to be nonpathogenic for man. Within the last decade, however, they have been documented as causing infection, particularly in young or debilitated persons. Acinetobacters have been found in cases of meningitis (1, 4,16,23), urethritis (12), urinary tract infections (17), vaginitis (20), conjunctivitis (5, 9), pneumonia (25), wound infections (15, 24), and septicemia (18). These bacteria are resistant to many antibiotics (1, 16). The drugs of choice for the treatment of acinetobacter infections are gentamicin, kanamycin, and polymyxin. Tetracycline has also been used when warranted by strain susceptibility. Recently Maderazo et al. reported that minocycline, a tetracycline analogue, is highly active against clinical isolates of A. calcoaceticus. It was effective for the treatment of bacteremic pneumonia caused by this species (14).In this report we compare the in vitro and in vivo efficacy of minocycline with tetracycline as well as with gentamicin and polymyxin.

Minocycline (7-dimethylamino-6-demethyl-6-deoxytetracycline) is a new semisynthetic tetracycline with potent activity against tetracycline-susceptible bacterial pathogens and unique activity against tetracycline-resistant staphylococci. Studies to determine the basis for this unique activity showed that, whereas tetracycline-resistant staphylococci took up less 3H-tetracycline than the susceptible cells, both the tetracycline-resistant and -susceptible cells accumulated equivalent amounts of "C-minocycline. In contrast, tetracyclineresistant Escherichia coli cells were relatively resistant to minocycline and accumulated less of both drugs than did the susceptible organisms. It is proposed that minocycline is effective against tetracycline-resistant staphylococci because of its ability to penetrate the cells sufficiently to reach inhibiting concentrations at sensitive reaction sites.

No abstract

Effect of ethambutol on nucleic acid metabolism in Mycobacterium smegmatis and its reversal by polyamines and divalent cations. J. Bacteriol. 89:1299-1305. 1965.-Mycobacterium smegmatis, harvested from cultures inhibited by ethambutol and then suspended in drug-free medium, exhibited a prolonged lag before growth resumed. Polyamines and magnesium ions shortened this lag. Polyamines and magnesium added to the culture increased the minimal inhibitory concentration of the drug and reversed the inhibitory effect of the drug, even when added after the drug had already inhibited growth. When ethambutol was added to a culture in its exponential phase of growth, synthesis of protein and deoxyribonucleic acid (DNA), as measured by incorporation of S5' and p32, continued for 3 hr at a rate slightly less than in the control cells and then essentially ceased. Synthesis of ribonucleic acid (RNA) was depressed, but it proceeded even after protein synthesis had ceased. Even though the synthesis of RNA continued, the net RNA decreased, and inhibited cells became deficient in RNA. Polyamines and divalent cations, which reverse the inhibitory effect of the drug, have been reported to be involved in nucleic acid turnover. These considerations suggested that ethambutol may exert its inhibitory effect by interfering with a function of cellulat polyamines and divalent cations in RNA metabolism. Ethambutol (dextro-2, 2'-[ethylenediimino]di-1-butanol) has specific antimycobacterial activity and is therapeutically effective in tuberculosis in animals (Thomas et al., 1961; Wilkinson et al., 1961) and in man (Bobrowitz, Garber, and Sukumalchantra, 1963). Reports on its in vitro and in vivo activity were reviewed by Robson and Sullivan (1963).