Macrolide antibiotics suppression

Fourteen-Membered-Ring Macrolide Antibiotics Suppress Gene Expression of Inflammatory Cytokines in Human Bronchial Epithelial Cells We evaluated the effects of macrolides on steady-state levels of IL-6 and IL-8 mRNA by Northern blot analysis [17, 60]. As shown in Fig. 13, bronchial epithelial cells expressed constitutive IL-8 mRNA, which was significantly upregulated by the cytokines such as IL-la, IL-1[3, and TNF-a. We reported that EM, CAM, and RXM inhibited steady-state levels of IL-6 and IL-8 expression in normal and immortalized bronchial epithelial cells [60, 62, 63]. This action appeared to be unique, because other antibiotics including a 16-membered ring macrolide JM... 

Fourteen-Membered Ring Macrolide Antibiotics Suppress Activation of Transcription Factors of Inflammatory Cytokines in Human Bronchial Epithelial Cells... 

Sirolimus is currently the only FDA-approved ToR inhibitor. One of its derivatives, everolimus, is in phase III clinical trials and has been approved for use in some European countries.30 Sirolimus is a macrolide antibiotic that has no effect on cal-cineurin phosphatase.11,31,32 Sirolimus inhibits T cell activation and proliferation by binding to and inhibiting the activation of the mammalian ToR, which suppresses cellular response to IL-2 and other cytokines (i.e., IL-4 and IL-15J.11,31 Studies have shown that sirolimus may be used safely and effectively with either cyclosporine or tacrolimus as a replacement for either azathioprine or mycophenolate mofetil.33 However, when using both sirolimus and cyclosporine as part of a patient s immunosuppressant therapy, because of a drug interaction between the two resulting in a marked increase in sirolimus concentrations, it is recommended to separate the sirolimus and cyclosporine doses by at least 4 hours. Sirolimus also can be used as an alternative agent for patients who do not tolerate calcineurin inhibitors due to nephrotoxicity or other adverse events.34... 

Tacrolimus is a macrolide antibiotic produced by the soil fungus Streptomyces tsukubaensis. It is one hundred times more potent than cyclosporine in vitro, but is equally as toxic if not more so. It suppresses both humoral and cell-media ted immune responses. Although chemically distinct from cyclosporine it elicits similar immunosuppressant effects. 

The suppressive activity of macrolide antibiotics on pro-inflammatory cjdokine production has also been shown in human peripheral blood monocytes, in which roxithromycin inhibited the in vitro production of interleukin-1 beta and tumor necrosis factor alpha (45). It also suppressed cytokine production after a prolonged pretreatment period in mice. In another mouse model both... 

Suzaki H, Asano K, Ohki S, Kanai K, Mizutani T, Hisamitsu T. Suppressive activity of a macrolide antibiotic, roxithromycin, on pro-inflammatory cytokine production in vitro and in vivo. Mediators Inflamm 1999 8(4-5) 199-204. 

To assess the effect of macrolide antibiotics on IL-8 production by inflamed airway epithelium, bronchial epithelial cells were obtained from 10 patients (3 with DPB, 5 with sinobronchial syndrome, 1 with nonatopic asthma associated with chronic sinusitis, and 1 with diffuse bronchiectasis, mean age of 54.8, all were non-or ex-smokers) under fiber optic bronchoscopy as previously reported [64, 65]. Spontaneous IL-8 release by airway epithelial cells from inflamed airways was significantly suppressed with the addition of EM and CAM, but not with ABPC in vitro [60]. Khair et al. [19] reported that EM inhibited release of IL-8 as well as of IL-6 from H. influenzae endotoxin-stimulated normal bronchial epithelial cells. 

Fig. 13. Northern blot analysis showing the inhibitory effect of macrolide antibiotics on IL-8 mRNA expression in normal human bronchial epithelial cells in culture. Total cellular RNAs were isolated, and equivalent doses of RNA (10 pg/lane) were electrophoresed on formaldehyde-denatured agarose gels. Northern blot analysis showed that IL-8 mRNA levels in cells stimulated by TNF-o were suppressed by pretreatment with EM, CAM, or RXM.

Candicidin production by Streptomyces griseus was inhibited by inorganic phosphate, which suppressed the biosynthesis of p-aminobenzoate, the starter unit for the synthesis of this 38-membered heptaene macrolide antibiotic [95]. P-aminobenzoic acid synthase (PABA synthase) catalyses the conversion of chorismic acid to PABA, which is a precursor to candicidin. 

Clindamycin binds exclusively to the 50S subunit of bacterial ribosomes and suppresses protein synthesis. Although clindamycin, erythromycin, and chloramphenicol are not structurally related, they act at sites in close proximity, and binding by one of these antibiotics to the ribosome may inhibit the interaction of the others. There are no clinical indications for the concurrent use of these antibiotics. Macrolide resistance due to ribosomal methylation by encoded enzymes also may produce resistance to clindamycin. However, because cUndamycin does not induce the methylase, there is cross-resistance only if the enzyme is produced con-stitutively. Clindamycin is not a substrate for macrolide efflux pumps thus, strains that are resistant to macrolides by this mechanism are susceptible to clindamycin. Altered metabolism occasionally causes clindamycin resistance. 

Nakamura, A., Naito, Y, Nakazawa, K., Ohara, K., and Sawai, T. (2000). Selective suppression of aminoglycoside 3 -phosphoiylating enzyme activities by macrolides—A study by using macrolide-resistant bacteria. Jpn. J. Antibiot. 53 (Suppl. A), 28-31. 

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