Deciphering the structure activity relationship, mode of action and uptake of isonitrile antibiotics in Gram-negative bacteria

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Infectious diseases caused by multiresistant pathogenic bacteria pose a major threat to public health. Especially Gram-negative bacteria such as Acinetobacter baumannii are of urgent need for novel drug development as almost no treatment options are left. Deciphering new antibiotics against these strains is challenged by the limited scope of currently exploited targets, diverse resistance strategies as well as a largely impermeable cell membrane. Thus, new approaches are needed to decipher novel modes of action (MoA) as well as clever uptake strategies. In the past, natural products have been a great source for potent antibiotics displaying various structural features even facilitating the entry into Gram-negative cells. Many of these compounds, despite potent antibiotic effects, have not been followed up. Given the current drought in the development pipeline their systematic characterization may lead to novel MoAs and corresponding drugs.We recently deciphered the MoA of xanthocillin, an isonitrile antibiotic discovered in 1948, with potent nM activity against A. baumannii. The molecule scavenges free heme in the bacterial cell and thereby dysregulates its biosynthesis leading to death by oxidative stress. We here would like to decipher how xanthocillin binds to heme by structure activity relationship studies. We thus aim to exploit the roles of the vinyl groups, the isonitriles as well as the aromatic ring system by the synthesis of diverse analogs. Crystallization with heme will unravel the binding mode and provide a rational for compound fine tuning. Moreover, we turn our attention to another isonitrile natural product antibiotic, B371, synthesize a chemical probe and investigate its cellular targets with our established chemical proteomic platform. As this molecule is structurally different and does only bear one isonitrile group, we anticipate a heme-independent MoA. Finally, we use tailored photoprobes to unravel the enigmatic uptake mechanisms of isonitriles into Gram-negative cells. Overall, these studies will contribute to a deeper understanding of a so far neglected group of antibiotics and their novel MoA.