In VitroInhibitory and Cytotoxic Activity of MFM 501, a Novel Codonopsinine Derivative, against Methicillin-ResistantStaphylococcus aureusClinical Isolates

Abstract

28 new pyrrolidine types of compounds as analogues for natural polyhydroxy alkaloids of codonopsinine were evaluated for their anti-MRSA activity using MIC and MBC value determination assay against a panel of S. aureus isolates. One pyrrolidine compound, MFM 501, exhibited good inhibitory activity with MIC value of 15.6 to 31.3 μg/mL against 55 S. aureus isolates (43 MRSA and 12 MSSA isolates). The active compound also displayed MBC values between 250 and 500 μg/mL against 58 S. aureus isolates (45 MRSA and 13 MSSA isolates) implying that MFM 501 has a bacteriostatic rather than bactericidal effect against both MRSA and MSSA isolates. In addition, MFM 501 showed no apparent cytotoxicity activity towards three normal cell lines (WRL-68, Vero, and 3T3) with IC50 values of >625 µg/mL. Selectivity index (SI) of MFM 501 gave a value of >10 suggesting that MFM 501 is significant and suitable for further in vivo investigations. These results suggested that synthetically derived intermediate compounds based on natural products may play an important role in the discovery of new anti-infective agents against MRSA.

In VitroEvaluations andIn VivoToxicity and Efficacy Studies of MFM501 against MRSA

“…Results of this time-kill study corroborated with previous MBC/MIC ratio values [1] that suggested MFM501 has a bacteriostatic mechanism of action against MRSA and MSSA isolates.…”

“…Additionally, by increasing its size, treated MRSA cells could also reduce their attachable surfaces against antibacterial compounds, hence, tolerating the stress conditions better than normal untreated cells [27]. This survival mechanism corroborated with earlier MBC/MIC ratio value of 32 for ATCC BAA-1688 against MFM501 [1]. Bacterial isolate that showed MBC/MIC ratio of ≥32 was considered tolerant or resistant towards the used anti-infective agent [1].…”

“…As described in previous study, MFM501 was synthesized in the Organic Synthesis Laboratory, Institute of Science (IOS), UiTM, Shah Alam, and identified using NMR and FTIR methods [ 1 ].…”

“…Currently, only a handful of antibiotics could inhibit this dangerous pathogen. Previously, we have discovered a synthetically derived pyrrolidone alkaloid, MFM501, exhibiting good inhibitory activity with MIC values between 15.6 and 31.3 µ g/ml against 38 MDR MRSA and 13 methicillin-sensitive S. aureus (MSSA) isolates with low cytotoxicity against three normal cell-lines (WRL-68, Vero, and 3T3) with IC 50 values at >625 µ g/ml [ 1 ].…”

New Access to Pyrano[2,3-<i>c</i>]pyrazole-3-carboxylates via Domino Four-Component Reaction and Their Antimicrobial Activity

“…Nevertheless, upon changing the original reaction protocol to domino type reaction manner furnished the title compounds and their derivatives from moderate to excellent yields. This library of compounds was then subjected to antimicrobial study as part of our endeavor on the screening of biologically active heterocyclic type compounds [15][16][17][18].…”