Exploring acyclic boronic derivatives as potent beta-lactamases inhibitors with broad spectrum activity

Background: Bacterial resistance has become a worldwide concern after the emergence of pan-resistant clinical isolates. beta-lactamases enzymes (BLs) represent one of the major mechanisms of bacterial resistance. Among them, the metallo depedent subclass (MBLs) are particularly worrisome, given their capability of hydrolysing beta-lactam antibiotics as well as any inhibitors currently in use. In particular, New Delhi metallo-BL-1 (NDM-1), the most prevalent type, is extremely efficient in inactivating nearly all-available antibiotics including last resort carbapenems. While for serine-beta-lactamases (SBLs) inhibitors are available in therapy, for MBLs no inhibitor have been at the present approved, compromising the efficacy of treatments of bacterial infections. Objectives: Our study aimed to characterize promising β-lactamases inhibitors with broad spectrum activity toward both serine and metallo BLs. We focused our attention on boron based benzothiophene derivatives and used a small library, based on such scaffold, to develop non-beta-lactam-like compounds able to bind BLs active site and inhibit their activity. Our choice has been encouraged by the recently approved serine BLs inhibitor vaborbactam and promising studies on cyclic boronic inhibitors. Methods: We performed an in depth structural and mechanicistic study of a small library of acyclic boronic benzothiophene derivatives with broad spectrum (both SBLs and MBLs) activity. Results: In solution kinetic characterization as well as extensive X-Ray crystallographic analysis of our best candidates have been performed and will be presented here.