Total Synthesis of the Four Stereoisomers of Cyclo(l-Trp-l-Arg) Raises Uncertainty of the Structures of the Natural Products and Invalidates Their Promising Antimicrobial Activities

International audience; New therapeutic options to combat the growing incidence of antimicrobial resistance 16 are urgently needed. A 2015 publication reported the isolation and biological evaluation of two 17 diketopiperazine natural products cyclo(L-Trp-L-Arg) (CDP 2) and cyclo(D-Trp-D-Arg) (CDP 3) 18 from an Achromobacter sp. bacterium, finding that the latter metabolite in particular exhibited 19 strong antibacterial activity towards a range of wound-related microorganisms and could syner-20 gise the action of ampicillin. Intrigued by these biological activities and noting inconsistencies in 21 the structural characterization of the natural products we have synthesized the four diastereomers 22 of cyclo(Trp-Arg) and evaluated them for antimicrobial and antibiotic enhancement properties. 23 Detailed comparison of spectroscopic data raises uncertainty regarding the structure of CDP 2 and 24 disproves the structure of CDP 3. In our hands, none of the four stereoisomers of cyclo(Trp-Arg) 25 exhibited detectable intrinsic antimicrobial properties towards a range of Gram-positive and 26 Gram-negative bacteria or fungi nor could they potentiate the action of antibiotics. These discrep-27 ancies in biological properties, compared to the activities reported in the literature, reveal that 28 these specific cyclic dipeptides do not represent viable templates for the development of new 29 treatments for microbial infections.