A total of 110 staphylococcal isolates from human skin were found to express a novel type of erythromycin resistance. The bacteria were resistant to 14-membered ring macrolides (MIC 32-128 mg/l) but were sensitive to 16-membered ring macrolides and lincosamides. Resistance to type B streptogramins was inducible by erythromycin. A similar phenotype, designated MS resistance, was previously described in clinical isolates of coagulase-negative staphylococci from the USA. In the UK, MS resistance is widely distributed in coagulase-negative staphylococci but was not detected in 100 erythromycin resistant clinical isolates of Staphylococcus aureus. Tests for susceptibility to a further 16 antibiotics failed to reveal any other selectable marker associated with the MS phenotype. Plasmid pattern analysis of 48 MS isolates showed considerable variability between strains and no common locus for the resistance determinant. In one strain of S. epidermidis co-resistance to tetracycline, penicillin and erythromycin (MS) was associated with a 31.5 kb plasmid, pUL5050 which replicated and expressed all three resistances when transformed into S. aureus RN4220. The MS resistance determinant was localised to a 1.9 kb fragment which was cloned on to the high-copy-number vector, pSK265. A constitutive mutant of S. aureus RN4220 containing the 1.9 kb fragment remained sensitive to clindamycin. This observation, together with the concentration-dependent induction (optimum 5 mg/l of erythromycin) of virginiamycin S resistance suggests that the MS phenotype is not due to altered expression of MLS resistance determinants (erm genes) but probably occurs via a different mechanism.
The extracellular lipids of the stratum corneum, which are comprised mainly of cholesterol, fatty acids, and ceramides, are essential for epidermal permeability barrier function. Moreover, disruption of the permeability barrier results in an increased cholesterol, fatty acid, and ceramide synthesis in the underlying epidermis. This increase in lipid synthesis has been shown previously to be due to increased activities of HMG-CoA reductase, acetyl-CoA carboxylase, fatty acid synthase and serine palmitoyl transferase, key enzymes of cholesterol, fatty acid, and ceramide synthesis, respectively. In the present study, we determined whether the mRNA levels for the key enzymes required for synthesis of these three classes of lipids increase coordinately during barrier recovery. By northern blotting, the steady-state mRNA levels for HMG-CoA reductase, HMG-CoA synthase, farnesyl pyrophosphate synthase, and squalene synthase, key enzymes for cholesterol synthesis, all increased significantly after barrier disruption by either acetone or tape stripping. Additionally, the steady-state mRNA levels of acetyl-CoA carboxylase and fatty acid synthase, required for fatty acid synthesis, as well as serine palmitoyl transferase, the rate-limiting enzyme of de novo ceramide synthesis, also increased. Furthermore, artificial restoration of the permeability barrier by occlusion after barrier disruption prevented the increase in mRNA levels for all of these enzymes, except farnesyl pyrophosphate synthase, indicating a specific link of the increase in mRNA levels to barrier requirements. The parallel increase in epidermal mRNA levels for the enzymes required for cholesterol, fatty acid, and ceramide synthesis may be due to one or more transcription factors that regulate lipid requirements for permeability barrier function in keratinocytes.
Cholesterol sulfate is a multifunctional sterol metabolite, produced in large amounts in squamous keratinizing epithelia. Because patients with recessive x-linked ichthyosis display not only a 10-fold increase in cholesterol sulfate, but also a 50% reduction in cholesterol, we assessed here whether cholesterol sulfate accumulation and/or cholesterol deficiency produce abnormal barrier function in recessive x-linked ichthyosis. Patients with recessive x-linked ichthyosis display both an abnormal barrier under basal conditions, and a delay in barrier recovery after acute perturbation, which correlate with minor abnormalities in membrane structure and extensive lamellar-phase separation. Moreover, both the functional and the structural abnormalities were corrected by topical cholesterol. Yet, topical cholesterol sulfate produced both a barrier abnormality in intact skin and extracellular abnormalities in isolated stratum corneum, effects largely reversed by coapplications of cholesterol. Together, these results suggest that cholesterol sulfate accumulation rather than cholesterol deficiency is responsible for the barrier abnormality. Despite the apparent importance of cholesterol sulfate-to-cholesterol processing for normal barrier homeostasis, neither steroid sulfatase activity nor mRNA levels are upregulated following acute perturbations. These results demonstrate both a potential role for cholesterol sulfate-to-cholesterol processing in normal permeability barrier homeostasis, and that basal levels of steroid sulfatase are sufficient to accommodate acute insults to the permeability barrier.
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