ABSTRACT
Aim: To determine the computer-predicted anticancer activity of mupirocin and to compare its activities with those determined for another polyene antibiotic, batumin. Materials & methods: Molecular docking, cytotoxicity assays, cell microscopy and cell cycle progression were studied in cancer and nontumorigenic cell lines. Results & conclusion: Cytotoxicity of mupirocin against several cancerous cell lines was detected with the highest one (IC50 = 5.4 µg/ml) against melanoma cell line. The profile of cytotoxicity of mupirocin was similar to that reported for batumin. Nevertheless, the morphology of cells treated with these antibiotics and alterations in cell cycle progression suggested possible dissimilarity in their mechanisms of action. Selective cytotoxicity of mupirocin against melanoma cells potentiates further studies to discover nontoxic drugs for melanoma prevention.
Subject(s)
Anti-Bacterial Agents/chemistry , Antineoplastic Agents/chemistry , Melanoma/drug therapy , Mupirocin/chemistry , Anti-Bacterial Agents/pharmacology , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Survival , Drug Design , Humans , Molecular Docking Simulation , Mupirocin/pharmacology , Organic Chemicals/chemistry , Organic Chemicals/pharmacology , Polyenes/chemistry , Polyenes/pharmacologyABSTRACT
AIM: To determine the computer-predicted anticancer activity of antibiotic batumin. MATERIALS & METHODS: Cytotoxicity assays, cell morphology microscopy and cell cycle progression were studied in cancer and nontumorigenic cell lines. An in vivo experiment on Lewis lung carcinoma (3LL)-transplanted mice was conducted to evaluate potential antimetastatic. RESULTS & CONCLUSION: Cytotoxicity against melanoma and lung carcinoma cells (IC50 ≈ 5 µg/ml) was detected. Hypercondensed chromatin and apoptotic body formation in batumin-treated cells suggested the induction of apoptosis supported also by an observed increase in the quantity of cells occupying the sub-G1 cell cycle phase. Twofold reduction in the number and volume of lung metastases in Lewis lung carcinoma (3LL)-bearing batumin-treated mice was demonstrated. Highly specific cytotoxicity of batumin against cancer cell lines potentiates further studies.
Subject(s)
Anti-Bacterial Agents/pharmacology , Apoptosis/drug effects , Polyenes/pharmacology , Pseudomonas/chemistry , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/therapeutic use , Binding Sites , Cell Line, Tumor , Female , G1 Phase Cell Cycle Checkpoints/drug effects , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Mice , Mice, Inbred C57BL , Molecular Docking Simulation , Organic Chemicals/chemistry , Organic Chemicals/pharmacology , Organic Chemicals/therapeutic use , Polyenes/chemistry , Proto-Oncogene Proteins c-mdm2/chemistry , Proto-Oncogene Proteins c-mdm2/metabolism , Pseudomonas/metabolism , Transplantation, HeterologousABSTRACT
Meticillin-resistant Staphylococcus aureus (MRSA) is a serious public health threat causing outbreaks of clinical infection around the world. Mupirocin is a promising anti-MRSA drug, however mupirocin-resistant strains of S. aureus are emerging at an increasing rate. The newly discovered antibiotic batumin may contribute to anti-MRSA therapy. The objective of this work was to identify possible molecular targets for batumin as well as mechanisms of its antistaphylococcal activity using computational molecular docking and by analysing the complete genome sequence of the batumin-producer Pseudomonas batumici UCM B-321. It was found that batumin acted very similarly to mupirocin by inhibiting aminoacyl tRNA synthetases. A previous hypothesis considering the trans-enoyl-CoA reductase FabI as a prime molecular target of batumin was rejected. However, indirect inhibition of fatty acid biosynthesis in sensitive bacteria does take place as a part of stringent response repression triggered by accumulation of uncharged tRNA molecules. Paralogues of diverse leucine-tRNA synthetases in the genome of P. batumici indicated that this protein might be the prime target of batumin. A batumin biosynthesis operon comprising 28 genes was found to be acquired through horizontal gene transfer. It was hypothesised that, in contrast to mupirocin, batumin could inhibit a broader range of aminoacyl tRNA synthetases and that acquired resistance to mupirocin might not endow S. aureus strains with resistance against batumin.
