Chalcone-Terpene Hybrids from Fissistigma litseifolium (King) Merr as Potential Carbapenemase Inhibitors

Resistance to carbapenems in Gram-negative bacteria is a major public health concern. This resistance is primarily mediated by carbapenemase enzymes, which hydrolyze and inactivate carbapenem antibiotics. These enzymes fall into two main categories: serine carbapenemases (e.g., OXA-48 and KPC-2) and zinc-dependent metallo-β-lactamases (e.g., NDM-1). Over recent years, their dissemination has dramatically increased worldwide, accompanied by the continuous emergence of novel variants. Notably, KPC-2 and OXA-48 are among the most prevalent carbapenemases. The current combinations of antibiotics and inhibitors available are insufficient to counteract the rapid spread of these enzyme variants. In this context, the bark extract of the Malasyan Fissistigma litseifolium (King) Merr, was selected following the screening of a large collection of plant extracts. This study describes and compares the metabolomic profile of this extract, for which no previous studies have been reported, with those of 13 other Fissistigma species. Phytochemical investigation resulted in the isolation of nine compounds, including three unreported natural products. Of these, fissisteifolin, a quinone, features a unique tetracyclic structure deriving from a chalcone and an uncommon monoterpene. Finally, fissistidin, an original chalcone-sesquiterpene dimer, exhibited 83% reduction in KPC-2 enzyme activity, establishing its potential as a candidate for developing novel carbapenemase inhibitors.