In Vitro Evaluations and in Vivo Toxicity and Efficacy Studies of MFM501 against MRSA

• Main Authors: Johari, S.A (Author), Mohamad Ridhwan, M.J (Author), Mohamed, A. (Author), Mohammat, M.F (Author), Mohtar, M. (Author), Sahdan, R. (Author), Syed Mohamad, S.A (Author)
• Format: Article
• Language: English
• Published: Hindawi Limited 2017
• Subjects: acute toxicity; animal; animal experiment; animal model; Animals; Anti-Bacterial Agents; antibiotic agent; antiinfective agent; Article; bacterial cell; cell membrane; cell surface; controlled study; drug effects; drug efficacy; extracellular matrix; human; Humans; in vitro study; in vivo study; methicillin resistant Staphylococcus aureus; Methicillin-Resistant Staphylococcus aureus; mfm 501; MFM501; Mice; microbial sensitivity test; Microbial Sensitivity Tests; microbiology; Microscopy, Electron, Scanning; minimum inhibitory concentration; mouse; nonhuman; pathogenicity; peritonitis; pyrrolizidine alkaloid; Pyrrolizidine Alkaloids; scanning electron microscopy; Staphylococcal Infections; Staphylococcus infection; toxicity testing; ultrastructure; unclassified drug
• Online Access: View Fulltext in Publisher; View in Scopus

 Previously we have discovered a synthetically derived pyrrolidone alkaloid, MFM501, exhibiting good inhibitory activity against 53 MRSA and MSSA isolates with low cytotoxicity against three normal cell-lines with IC50 values at >625 μg/ml. Time-kill assay, scanning electron microscopy (SEM) analysis, in vivo oral acute toxicity test, and mice peritonitis model were carried out in this study. In the time-kill study, MFM501 showed a less than 3 log10 decrease in bacterial colony concentration value (CFU/ml) which represented a bacteriostatic action while displaying a time-dependent inhibitory mechanism. Following that, SEM analysis suggested that MFM501 may exert its inhibitory activity via cytoplasmic membrane disruption. Moreover, MFM501 showed no toxicity effect on treated mice at an estimated median acute lethal dose (LD50) value of more than 300 mg/kg and less than 2000 mg/kg. For the efficacy test, a mean effective dose (ED50) of 87.16 mg/kg was obtained via a single dose oral administration. Our data demonstrated that MFM501 has the potential to be developed further as a new, safe, and effective oral-delivered antibacterial agent against MRSA isolates. © 2017 Saiful Azmi Johari et al.