Abstract
Difficulties involved in treating drug-resistant pathogens have created a need for new therapies. In this study, we investigated the possibility of using oleanolic acid (OA), a natural pentacyclic triterpenoid, as a natural adjuvant for antibiotics against Acinetobacter baumannii. High concentrations of OA can kill cells, partly because it generates reactive oxygen species. Measurement of the fractional inhibitory concentration (FIC) for OA and time-kill experiments demonstrated that it only synergizes with aminoglycoside antibiotics (e.g., gentamicin, kanamycin). Other classes of antibiotics (e.g., ampicillin, rifampicin, norfloxacin, chloramphenicol, and tetracycline) have no interactions with OA. Microarray and quantitative reverse transcription-PCR analysis indicated that genes involved in ATP synthesis and cell membrane permeability, the gene encoding glycosyltransferase, peptidoglycan-related genes, phage-related genes, and DNA repair genes were upregulated under OA. OA highly induces the expression of adk, which encodes an adenylate kinase, and des6, which encodes a linoleoyl-CoA desaturase, and deletion of these genes increased FICs; these observations indicate that adk and des6 are involved in the synergism of OA with aminoglycosides. Data obtained using 8-anilino-1-naphthalenesulfonic acid, fluorescence-conjugated gentamicin, and membrane fatty acid analysis indicates that adk and des6 are involved in changes in membrane permeability. Proton-motive force and ATP synthesis tests show that those genes are also involved in energy metabolism. Taken together, our data show that OA boosts aminoglycoside uptake by changing membrane permeability and energy metabolism in A. baumannii.
Highlights
Public health risk caused by multidrug-resistant (MDR) bacteria has become a serious problem on a global scale
Microarray and quantitative reverse transcription-PCR analysis indicated that genes involved in ATP synthesis and cell membrane permeability, the gene encoding glycosyltransferase, peptidoglycan-related genes, phage-related genes, and DNA repair genes were upregulated under oleanolic acid (OA)
We found that OA reduced the Minimum inhibitory concentration (MIC) of aminoglycosides but did not affect the MICs of other types of antimicrobial agents (Table 1)
Summary
Public health risk caused by multidrug-resistant (MDR) bacteria has become a serious problem on a global scale. Aminoglycosides are highly potent, broad-spectrum antibiotics that have been traditionally used for the treatment of serious gram-negative infections [6, 7] They kill bacteria by inhibiting protein synthesis via binding to 16S rRNA and by disrupting bacterial cell membrane integrity [8]. Aminoglycosides combined with β-lactam antibiotics, which inhibit cell wall synthesis, may be the most reliable therapy for the treatment of MDR Enterococcus species [9]. Side effects such as ototoxicity, nephrotoxicity, and organ failure remain serious problems resulting from the clinical use of aminoglycosides [10]. It is necessary to find novel therapies with fewer side effects and greater therapeutic action than the options currently available
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