Synergy and mechanism of action of α-mangostin and ceftazidime against ceftazidime-resistant Acinetobacter baumannii

To address the resistance of Acinetobacter baumannii to beta-lactam antibiotics, combination therapy between different antibiotic classes is increasingly used. The antibacterial activity of alpha-mangostin (AMT) alone or in combination with ceftazidime (CTZ) was investigated against ceftazidime-resistant A. baumannii DMST 45378 (CRAB). Initial screening showed that A. baumannii strains possessed AmpC beta-lactamase (AmpC), extended-spectrum beta-lactamase (ESBL) and metallo-beta-lactamases (MBL). Minimum inhibitory concentrations (MICs) of all test agents were > 800 mu g ml(-1) against CRAB. The combination of AMT/CTZ exhibited a fractional inhibitory concentration index (FICI) of < 0.35 suggestive of synergy. Time-kill curves showed that the AMT/CTZ combination was significantly more efficient (P < 0.01) at reducing CRAB than the individual components. Structural analysis revealed that AMT/CTZ-treated cells exhibited increased cell volume, increased cytoplasmic and outer membrane permeability and a decrease in outer membrane peptidoglycan-associated protein (OMPG) bands. In addition, it was shown that Type IV beta-lactamase was inhibited by AMT. The data suggest that AMT in combination with CTZ is synergistic and efficient against CRAB. The data also indicate that the AMT/CTZ combination may target multiple structures on the bacterial cell surface. This represents the first report of this effect on CRAB and could potentially be expanded into invivo studies.