Extended-spectrum β-lactamase (ESBL)-producing bacteria pose a big challenge in clinical practices, warranting a new therapeutic strategy. In this study, methanol extract of the marine cyanobacterium Oscillatoria acuminata NTAPC05 was fractionated under bioassay guidance and the fractions were tested against three well-characterized ESBL-producing bacteria Escherichia coli U655, Stenotrophomonas maltophilia B929 and Enterobacter asburiae B938. Out of the four HPLC fractions, fraction 2 showed bactericidal activity against all the three ESBL producers much more efficiently (MIC 100 μg ml−1) than the fourth-generation cephalosporin (MIC >125 μg ml−1). The active fraction was subjected to time-kill test at concentrations of 1/2 × MIC, 1 × MIC and 2 × MIC, and the results substantiated the bactericidal property of the fraction against the ESBL producers. Spectral analysis revealed monogalactosyldiacylglycerol containing a palmitoyl (MGDG-palmitoyl), being reported for the first time, as the active fraction, and its bactericidal property against ESBL producers was determined. The active fraction appears to damage the bacterial membrane leading to lysis of the cell, as revealed in confocal laser scanning microscopy (CLSM) analysis, that was confirmed in scanning electron microscopic analysis. Cytotoxicity assay revealed the O. acuminata compound to be safe to a normal cell line HEK293 (human embryonic kidney cell). The in silico analysis of MGDG-palmitoyl revealed two successive H-bonding interactions with Leu198 of TEM1 β-lactamase. Taken together, the MGDG-palmitoyl from O. acuminata NTAPC05 offers potential to develop analogs as a therapeutic for bacteremia caused by ESBL producers.
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We are grateful to Dr Hemalatha Rao, Medwin Hospital (Hyderabad, India) for providing the clinical isolates. We thank the Deanship of Scientific Research at King Saud University for funding the work through the research group project (Ref No RGP-VPP-332). We thank DST- PURSE scheme (Project Ref No- SR/FT/LS-113/2009) of the Department of Science and Technology (DST), New Delhi, India, for the Confocal Laser Scanning Microscopy facility. This work was otherwise supported by the Project (Ref No BT/PR4815/AAQ/3/587/2012, BT/PR6619/PBD/26/310/2013, BT/IN/Indo-UK/SuBB/23/NT/2013 and BT/PR7005/PBD/ 26/357/2015) sanctioned by the Department of Biotechnology (DBT), New Delhi, India.
AP and NT performed most of the experiments and drafted the manuscript; MUR carried out the sample collection from humans and identified the bacterial strains; KPMN investigated the antibiotic resistance pattern and identified ESBL producers; NR contributed to the amplification of ESBL genes and interpretation of results; SS obtained the microphotograph and identification of cyanobacterium; MYMI contributed in 16S DNA amplification in ESBL producers; NSA, CA and SAA equally contributed in the analysis and interpretation of data; MAA carried out the cell line study, coordinated the manuscript drafting and language editing. All authors approved the final version of the manuscript.
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Supplementary Information accompanies the paper on The Journal of Antibiotics website (http://www.nature.com/ja)
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