Abstract
Recent decades have witnessed a dramatic increase of multidrug resistant (MDR) bacteria, compromising the efficacy of available antibiotics, and a continual decline in the discovery of novel antibacterials. We recently reported the first library of benzo[b]thiophen-2-ylboronic acid inhibitors sharing broad spectrum activity against β-lactamases (BLs). The ability of these compounds to inhibit structurally and mechanistically different types of β-lactamases has been here structurally investigated. An extensive X-ray crystallographic analysis of boronic acids (BAs) binding to proteins representative of serine BLs (SBLs) and metallo β-lactamases (MBLs) have been conducted to depict the role played by the boronic group in driving molecular recognition, especially in the interaction with MBLs. Our derivatives are the first case of noncyclic boronic acids active against MBLs and represent a productive route toward potent broad-spectrum inhibitors.
Highlights
We recently reported the first library of benzo[b]thiophen-2-ylboronic acid inhibitors sharing broad spectrum activity against β-lactamases (BLs)
W orldwide bacterial resistance is mining the efficacy of available antibiotics and the continuous dissemination of pan resistant bacteria represents a real menace to public health.[1]
While inhibitors are available in therapy for serine BLs (SBLs), for MBLs no inhibitor has been at the present approved, menacing the efficacious treatment of bacterial infections.[7−9] daily infections caused by clinical strains coproducing extended spectrum BLs (ESBLs) and carbapenemases are not susceptible to available antibiotics and require last line antibacterial agents, e.g., colistin.[10,11]
Summary
If cyclic BAs were recently identify as first reported dual inhibitors,[23] we recently disclosed a small library of benzo[b]thiophen-2-ylboronic acids active as the first noncyclic BAs active against all four BLs classes and with biological activity vs clinical strains (Table 1, see Supporting Information).[24]. The BA mechanism of action has been largely disclosed for SBLs and involves the covalent and reversible binding to the catalytic serine;[19,29,30] for MBLs NDM-1, our evidence shows that these derivatives maintain the correct Zn coordination as per natural β-lactam substrates and explains their ability to overcome active site architecture peculiarities along BLs classes (S7). They represent valuable leads for the development of broad-spectrum inhibitors
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