New classes of Gram-positive selective antibacterials: Inhibitors of MRSA and surrogates of the causative agents of anthrax and tuberculosis

Abstract

An antimicrobial phenolic stilbene, (E)-3-hydroxy-5-methoxystilbene, 1 was recently isolated from the leaves of Comptonia peregrina (L.) Coulter and shown to possess inhibitory activity against several Gram-positive bacteria, including isolates of methicillin-resistant Staphylococcus aureus (MRSA), Mycobacterium bovis BCG, and avirulent Bacillusanthracis (Sterne strain), among others. These results prompted the design and synthesis of two new classes of compounds, phenoxystyrenes and phenothiostyrenes, as analogs of the natural antimicrobial stilbene. These and additional stilbenoid analogs were synthesized using new, efficient, copper-mediated coupling strategies. Minimum inhibitory concentration (MIC) antimicrobial assays were performed on all compounds prepared. These preliminary structure-activity relationship studies indicated that both new classes of synthetic analogs, as well as the stilbenes, show promising activity against Gram-positive bacteria when at least one phenolic moiety is present, but not when absent. The potencies of the phenolic phenoxystyrenes and phenothiostyrenes were found to be comparable to those of the phenolic stilbenes tested.

Docking into Mycobacterium tuberculosis Thioredoxin Reductase Protein Yields Pyrazolone Lead Molecules for Methicillin-Resistant Staphylococcus aureus

“…Tetracycline, oxacillin, and vancomycin (Sigma-Aldrich, St. Louis, MO, USA) were included as control antibiotics and correlated with established MIC values for the ATCC strains. All anti- Mycobacterium MIC evaluations were performed using MIC assays in Middlebrook 7H9 broth with 10% oleic acid albumin dextrose complex (OADC) as previously described [21]. Isoniazid was used as the positive control for the mycobacterial MICs.…”

Synthesis and minimum inhibitory concentrations of SK-03-92 against Staphylococcus aureus and other gram-positive bacteria

“…By screening extracts of medicinal plants and fungi (wild mushrooms) for new molecules that might be effective in treating clinically significant bacterial infections, a recent study identified (E)-3-hydroxy-5-methoxystilbene in the leaves of the shrub Comptonia peregrina (L.) Coulter (''sweet fern'') [7], which was used medicinally in the past by Native Americans. This lead compound showed promising activity against S. aureus, including MRSA.…”

“…The (E)-3-(2-(benzo[b]thiophen-2-yl)vinyl)-5-methoxyphenol structure labeled SK-03-92 shown in Fig. 1 was verified using mass spectrometry, infrared spectrometry, and nuclear magnetic resonance spectrometry as previously described [7].…”

“…Tetracycline, ciprofloxacin, and erythromycin controls were included as control antibiotics for the gram-positive bacteria MICs and correlated with established MIC values. All anti-Mycobacterium activity evaluations (except for the anti-Mycobacterium tuberculosis assays) were performed using MIC assays in Middlebrook 7H9 broth with 10% oleic acid albumin dextrose complex (OADC) as previously described [7]. Rifampin was used as the positive control for the mycobacterial MICs.…”

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“…Recently, additional properties of resveratrol have been documented, such as radical scavenging, antioxidant activity 14,16 , neuroprotection 14,17 , antiviral activity 14,18 , antibacterial activity [19][20][21] , antitubercular activity [22][23][24] . Suitable substituted cisstilbene derivatives are characterized by potent inhibitory activity on COX-2, quite similarly with that observed for a variety of vicinal diarylheterocycles, among which important antiinflammatory drugs, like celecoxib and valdecoxib, are found 25 .…”