Discovery and characterization of aryl isonitriles as a new class of compounds versus methicillin- and vancomycin-resistant Staphylococcus aureus

Abstract

Methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA) have emerged as a global health concern. A new class of compounds featuring an aryl isonitrile moiety has been discovered that exhibits potent inhibitory activity against several clinically-relevant MRSA and VRSA isolates. Structure-activity relationship studies have been conducted to identify the aryl isonitrile group as the key functional group responsible for the observed antibacterial activity. The most potent antibacterial aryl isonitrile analogs (MIC 2 µM) did not show any toxicity against mammalian cells up to a concentration of 64 µM.

Investigation of aryl isonitrile compounds with potent, broad-spectrum antifungal activity

“…The biaryl isonitriles 19 and 20 are potent antifungal compounds against C. albicans with 0.5 μM and 2 μM MIC values respectively and the naphthyl group decreased the potency about 4-fold. Interestingly, in our previous studies, 14 both 19 and 20 only showed weak or even no antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA) strains. Compound 32 with a saturated two-carbon linker between the two aryl groups showed potent anti C. albicans activity as well (MIC = 0.5 μM).…”

“…Interestingly, analogues exhibiting the most potent antifungal activity (including 7, 11, 19, 20 , and 32 ) possessed only modest or weak antibacterial activity against drug-resistant S. aureus. 14 This information is critical to help guide the synthesis of future aryl isonitrile analogues to improve their specificity as antifungal agents.…”

“…In the search for new antimicrobial drug scaffolds, we recently discovered synthetic aryl isonitrile compounds that exhibit notable antibacterial activity against drug-resistant Staphylococcus aureus . 14 It has been shown that natural product compounds containing the isonitrile functional group can possess dual antibacterial and antifungal activity, particularly against C. albicans. 15, 16 Per this observation, the present study investigates the structure-activity relationship of our synthetic aryl isonitrile compounds (Figure 1) as antifungal agents, examines their spectrum of activity against pertinent species of Candida, Cryptococcus, and Aspergillus, and evaluates the most promising compounds' toxicity against mammalian cells.…”

“…The biaryl isonitriles ( 19, 20 ) were synthesized from a sequence of Suzuki cross coupling, formamide formation, and dehydrate. 14 …”

Bazı taurinamit türevi bileşiklerin sentezi ve antimikrobiyel etkileri

“…In fact, there is a lack in development of new drugs and mortality rates are increasing due to bacterial infections. As a consequence, antibacterial drug development studies become an urgent area in medicinal chemistry (2,3). The strategies for developing new compounds, mostly based on synthetic modifications of natural antibiotics and synthetic antibacterials like sulfonamides (4).…”