New isocyanide antibiotics with broad spectrum against Gram-negative pathogens produced by cultures of an unidentified fungus

Infections caused by bacteria are a growing medical concern as many of these pathogens are resistant to various common antibiotics. The complex architecture of Gram-negative bacteria enables a wide diversity of antibiotic resistance mechanisms and the development of new drugs active against these pathogens has become a major medical concern. In our continuous search for new and biologically active natural products for medicinal applications or as leads for the development of new therapies, we have isolated a new family of isocyanide containing natural products with broad spectrum antibacterial activity (MDN-0057, MDN-0058, MDN-0059 and MDN-0060). These compounds were isolated from acetone extracts of cultures of the producer fungal strain by SP207ss resin column chromatography followed by semi-preparative HPLC of the active fractions. Structural elucidation of the family of compounds was based on 1D and 2D NMR and High Resolution Mass Spectrometry (ESI-TOF). The absolute configuration of all compounds was determined by a combination of techniques, including analysis of coupling constants values NOESY correlations, Mosher derivatization, ECD and conformational analysis. This family of natural products displayed broad spectrum antibacterial activity against Gram-negative pathogens, with MICs values between 2 µg/mL and 16 µg/mL against Acinetobacter baumannii, Pseudomonas aeruginosa and Escherichia coli, including strains resistant to clinically used antibiotics. Hence, they represent an innovative scaffold for developing new drugs against bacterial infections produced by these pathogens. Moreover their discovery points out that nature continue to be an abundant source of unprecedented and chemically diverse antibacterial leads.

Keywords: MDN-0057, isocyanide, Gram-negative, fungus, absolute configuration