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

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Abstract

To address the resistance of Acinetobacter baumannii to β-lactam antibiotics, combination therapy between different antibiotic classes is increasingly used. The antibacterial activity of α-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 β-lactamase (AmpC), extended-spectrum beta-lactamase (ESBL) and metallo-β-lactamases (MBL). Minimum inhibitory concentrations (MICs) of all test agents were >800 μg 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 β-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 in vivo studies.

Significance and Impact of the Study

Significance and Impact of the Study:Acinetobacter baumannii strains cause serious infections, patient mortality, and have been reported to rise of multidrug resistance. This article represents the first report of using α-mangostin plus ceftazidime against these resistant strains and its mechanism of action. α-mangostin has no cytotoxic effects. Therefore, α-mangostin has strong potential for development as a useful, novel adjunct phytopharmaceutical to ceftazidime synergistically for the treatment of these strains. The synergy approach could potentially be a novel tool to combat the resistant strains.

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