The frequency and mechanism of spontaneous resistance to sulbactam combined with the novel {beta}-lactamase inhibitor ETX2514 in clinical isolates of Acinetobacter baumannii [PublishAheadOfPrint]

The novel diazabicyclooctenone ETX2514 is a potent, broad spectrum serine β-lactamase inhibitor that restores sulbactam activity against resistant Acinetobacter baumannii. The frequency of spontaneous resistance to sulbactam-ETX2514 in clinical isolates was found to be 7.6x10^-10 to <9.0x10^-10 at 4x MIC and mapped to residues near the active site of PBP3. Purified mutant PBP3 proteins demonstrated reduced affinity for sulbactam. In a sulbactam-sensitive isolate, resistance also mapped to stringent response genes associated with resistance to PBP2 inhibitors, suggesting that, in addition to β-lactamase inhibition, ETX2514 may also enhance sulbactam activity in A. baumannii via inhibition of PBP2.

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