Investigating the Antibacterial Effects of Synthetic Gamma-Lactam Heterocycles on Methicillin-Resistant <i>Staphylococcus aureus</i> Strains and Assessing the Safety and Effectiveness of Lead Compound MFM514
Saiful Azmi Johari,
Mastura Mohtar,
Mohd Fazli Mohammat,
Fatin Nur Ain Abdul Rashid,
Muhamad Zulfaqar Bacho,
Azman Mohamed,
Mohamad Jemain Mohamad Ridhwan,
Sharifah Aminah Syed Mohamad
Affiliations
Saiful Azmi Johari
Bioactivity Programme, Natural Products Division, Forest Research Institute Malaysia (FRIM), Kepong 52109, Selangor, Malaysia
Mastura Mohtar
Bioactivity Programme, Natural Products Division, Forest Research Institute Malaysia (FRIM), Kepong 52109, Selangor, Malaysia
Mohd Fazli Mohammat
Organic Synthesis Laboratory, Institute of Science, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, Puncak Alam, Kuala Selangor 42300, Selangor, Malaysia
Fatin Nur Ain Abdul Rashid
Organic Synthesis Laboratory, Institute of Science, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, Puncak Alam, Kuala Selangor 42300, Selangor, Malaysia
Muhamad Zulfaqar Bacho
Organic Synthesis Laboratory, Institute of Science, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, Puncak Alam, Kuala Selangor 42300, Selangor, Malaysia
Azman Mohamed
Bioactivity Programme, Natural Products Division, Forest Research Institute Malaysia (FRIM), Kepong 52109, Selangor, Malaysia
Mohamad Jemain Mohamad Ridhwan
Pharmacy Programme, Sultan Azlan Shah Allied Health Sciences College, Tanjung Rambutan 31250, Perak, Malaysia
Sharifah Aminah Syed Mohamad
Faculty of Applied Sciences, Universiti Teknologi MARA (UiTM), Shah Alam 40450, Selangor, Malaysia
Methicillin-resistant Staphylococcus aureus (MRSA) continues to be one of the main causes of hospital-acquired infections in all regions of the world, while linezolid is one of the only commercially available oral antibiotics available against this dangerous gram-positive pathogen. In this study, the antibacterial activity from 32 analogues of synthetic gamma-lactam heterocycles against MRSA was determined. Amongst screened analogues for the minimum inhibitory concentration (MIC) assay, compound MFM514 displayed good inhibitory activity with MIC values of 7.8–15.6 µg/mL against 30 MRSA and 12 methicillin-sensitive S. aureus (MSSA) clinical isolates, while cytotoxicity evaluations displayed a mean inhibitory concentration (IC50) value of > 625 µg/mL, displaying a potential to becoming as a lead compound. In subsequent animal studies for MFM514, a single-dose oral acute toxicity test revealed an estimated mean lethal dose (LD50) value of 50) value of 29.39 mg/kg was obtained via oral administration. These results suggest that gamma-lactam carbon skeleton, particularly MFM514, is highly recommended to be evaluated further as a new safe and efficacious orally delivered antibacterial agent against MRSA.
