Early Insights into the Interactions of Different β-Lactam Antibiotics and β-Lactamase Inhibitors against Soluble Forms of Acinetobacter baumanniiPBP1a and Acinetobactersp. PBP3

ABSTRACTAcinetobacter baumanniiis an increasingly problematic pathogen in United States hospitals. Antibiotics that can treat A. baumanniiare becoming more limited. Little is known about the contributions of penicillin binding proteins (PBPs), the target of β-lactam antibiotics, to β-lactam–sulbactam susceptibility and β-lactam resistance in A. baumannii. Decreased expression of PBPs as well as loss of binding of β-lactams to PBPs was previously shown to promote β-lactam resistance in A. baumannii. Using an in vitroassay with a reporter β-lactam, Bocillin, we determined that the 50% inhibitory concentrations (IC50s) for PBP1a from A. baumanniiand PBP3 from Acinetobactersp. ranged from 1 to 5 μM for a series of β-lactams. In contrast, PBP3 demonstrated a narrower range of IC50s against β-lactamase inhibitors than PBP1a (ranges, 4 to 5 versus 8 to 144 μM, respectively). A molecular model with ampicillin and sulbactam positioned in the active site of PBP3 reveals that both compounds interact similarly with residues Thr526, Thr528, and Ser390. Accepting that many interactions with cell wall targets are possible with the ampicillin-sulbactam combination, the low IC50s of ampicillin and sulbactam for PBP3 may contribute to understanding why this combination is effective against A. baumannii. Unraveling the contribution of PBPs to β-lactam susceptibility and resistance brings us one step closer to identifying which PBPs are the best targets for novel β-lactams.