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Enhanced dereplication of fungal cultures via use of mass defect filtering.

ABSTRACT: Effective and rapid dereplication is a hallmark of present-day drug discovery from natural sources. This project strove to both decrease the time and expand the structural diversity associated with dereplication methodologies. A 5 min liquid chromatographic run time employing heated electrospray ionization (HESI) was evaluated to determine whether it could be used as a faster alternative over the 10 min ESI method we reported previously. Results revealed that the 5 min method was as sensitive as the 10 min method and, obviously, was twice as fast. To facilitate dereplication, the retention times, UV absorption maxima, full-scan HRMS and MS/MS were cross-referenced with an in-house database of over 300 fungal secondary metabolites. However, this strategy was dependent upon the makeup of the screening in-house database. Thus, mass defect filtering (MDF) was explored as an additional targeted screening strategy to permit identification of structurally related components. The use of a dereplication platform incorporating the 5 min chromatographic method together with MDF facilitated rapid and effective identification of known compounds and detection of structurally related analogs in extracts of fungal cultures.

SUBMITTER: Paguigan ND

PROVIDER: S-EPMC5407915 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Enhanced dereplication of fungal cultures via use of mass defect filtering.

Paguigan Noemi D ND El-Elimat Tamam T Kao Diana D Raja Huzefa A HA Pearce Cedric J CJ Oberlies Nicholas H NH

The Journal of antibiotics 20170111 5

Effective and rapid dereplication is a hallmark of present-day drug discovery from natural sources. This project strove to both decrease the time and expand the structural diversity associated with dereplication methodologies. A 5 min liquid chromatographic run time employing heated electrospray ionization (HESI) was evaluated to determine whether it could be used as a faster alternative over the 10 min ESI method we reported previously. Results revealed that the 5 min method was as sensitive as ...[more]

PMID: 28074050

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Project description:The Guan-Xin-Shu-Tong capsule (GXSTC) is a well-known traditional Chinese medicine that is used for the treatment of coronary heart disease. Despite its common use in China, basic pharmacological research on its active components is limited. A comprehensive analytical method using quadrupole-time-of-flight mass spectrometry (Q-TOF/MS), specifically with the Triple TOF 5600 platform, was developed to characterize the compounds in the GXSTC powder itself (in vitro) as well as the active components in healthy and heart disease model rats after its oral administration (in vivo). The 5600 platform was operated in both positive and negative ion modes, before the raw data were processed using the extracted ion chromatography (EIC), mass defect filtering (MDF) and fragment filtering (FF) techniques. With the aid of reference compounds for retention time and fragment ion comparisons, 18 compounds were unambiguously identified in vitro. An additional 56 other compounds were tentatively characterized using the accurate quasi-molecular ion mass and Tandem mass spectrometry (MS/MS) fragmentation pattern strategies. Among them, 30 compounds were characterized based on the MDF and FF approaches. Normal rats in addition to hyperlipidemic (HL) and acute blood stasis (ABS) model rats were given a single oral dose of GXSTC solution for subsequent blood analysis at 1 and 2 h after administration. A total of 24 prototypecomponents and 20 metabolites derived from GXSTC were differentially detected across the three animal groups, including the absence of four phase II phenolic acid metabolites in the ABS group and the presence of three diterpenoid-related metabolites exclusive to the HL group. The use of reference compounds as well as the mass defect and fragment-filtering strategies were critical to identify GXSTC compounds in vitro and in vivo. This can be used for further quality control and pharmacological studies aimed at characterizing the active and potential beneficial compounds of this ancient medicine.

Project description:RationaleOrganophosphate flame retardants (OPFRs) are a class of flame retardants widely found in environmental and biological matrices that have been extensively studied due to their adverse health effects in humans. OPFRs are loosely bound chemicals that can detach from treated products and be released into indoor and outdoor environments, where they have the potential to further undergo transformation and degradation processes, in particular the chlorinated OPFRs (Cl-PFRs). Their detection remains a moving target for analysts, and traditional targeted mass spectrometry methods are suitable only for those compounds with authentic standards.MethodsMass defect filter (MDF) is a strategy to filter molecular features using thresholds applied to the mass defect value of a target ion or molecular feature of interest. We have developed an MDF strategy for the detection and tentative identification of twelve potential Cl-PFR transformation products in a study mixture of six known Cl-PFRs using MS/MS data acquired on a high-resolution mass spectrometer. Most compounds in the Cl-PFRs family share a ClO4 P group as a core structure, of which modification results in a significant shift in the exact masses of the resulting compounds but show only a minimal shift in their mass defects. Subsequently, the MDF strategy was employed to tentatively identify Cl-PFRs retrospectively in six human urine samples that had previously been analyzed.ResultsMDF in combination with product ion filtering for the characteristic [H2 O3 P]+ and [H4 O4 P]+ ions and neutral loss filtering for the characteristic Cn H2n-x Clx group resulted in revealing suspects and homologues in the Cl-PFRs family. Furthermore, the MDF of the product ions detected additional Cl-PFR-related compounds that differed significantly in the exact masses of both precursor and product ions but had minimal shift in the mass defects of product ions. The mass defect of one or more common product ions helped to detect a few Cl-PFR analogs that had not been identified by MDF of the core structure precursor ion.ConclusionsMDF helped to detect some Cl-PFRs present in lower concentrations, which went undetected without data filters. MDF also helped to detect chromatographic peaks for Cl-PFR homologues that are likely structural analogs that resulted from impurities and/or derivatives and transformation products. The methodology was applied to demonstrate and tentatively detect known and suspect Cl-PFRs in human urine samples retrospectively.

Dataset Information

Enhanced dereplication of fungal cultures via use of mass defect filtering.

Publications

Enhanced dereplication of fungal cultures via use of mass defect filtering.

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