Earlier studies on the susceptibility of L-forms to antibiotics were made by Ward et al.6 and other workers7. However, in most cases use was not made of stable L-forms but rather the unstable -L-forms or spheroplasts or mixtures of these forms, all of which possess cell walls or fragments thereof. With Proteus mirabilis it is possible to investigate the behaviour of the cell as a whole and of the 'cell contents' (protoplast) in the presence of substances such as antibiotics. In my experiments, erythromycin, carbomycin (magnamycin), spiramycin, oleandomycin, leucomycin and angolamycin were tested by an agar diffusion method using double-layer plates, the upper layer being inoculated with either the normal rod forms or the stable L-forms. The antibiotics were added to holes (0.05 ml.) to produce zones of inhibition after diffusion. The concentrations of the test solutions were 1,000, 100, 10 and 1 mg/ml. Table 1 shows the results.Table 1. ACTION OF MACROLIDES ON Proteus mirabilis (STRAINS VI AND 52) AND THEIR STABLE L-FORMS (Figures represent the minimal inhibitory concentrations ing/ml.) VI 52 X-form VI L-foTm. 52Erythromycin Magnamycin Leucomycin Spiramycin Oleandomycin Angolamycin ^ 1,000>1,000>1,000>1,000>1,000>1,000 (&1,000>1,000>1,000>1,000>1,000>1,000<1<1<1<10<10<10<1<1<1<10<10<10 It can be seen that the macrolides act selectively on the stable L -forms while the parent strains are virtually unaffected.For comparison, some other antibiotics have been tested by the same method. Netropsin, neomycin, kanamycin, paromomycin, streptomycin, novobiocin, chloramphenicol, chlortetracycline and oxytetracycline inhibited at relatively high concentrations both the bacillary forms and the .L-forms, the latter being commonly slightly more sensitive. Grisein and actidione, as well as mycostatin, trichomycin and some other polyene antibiotics, did not affect any of the forms of Proteus. The strikingly selective action of the macrolides as a group may be due to the absence of the cell walls in the L -forms. In contrast to many other antibiotics, the molecules of these drugs are evidently prevented by the walls from freely entering the cell contents of the normal rod forms. It is unlikely that the observations can be explained by basic differences in the metabolism of Proteus and its L-forms because the reactions so far investigated have been shown to be essentially the same4. Furthermore, the possibility of selective enzymatic inactiva-tion of the macrolides by the rods was excluded prolonged incubation of the antibiotics with Proteus rods did not lead to specific loss of activity.It is suggested that within the commonly used range of concentrations the marked natural resistance of Proteus mirabilis to macrolides is due to the inability of the substances to penetrate the cell walls of the normal rods in effective amounts and is not due to insensitivity of the metabolism of Proteus.