A major goal in natural product discovery programs is to rapidly dereplicate known entities from complex biological extracts. We demonstrate here that molecular networking, an approach that organizes MS/MS data based on chemical similarity, is a powerful complement to traditional dereplication strategies. Successful dereplication with molecular networks requires MS/MS spectra of the natural product mixture along with MS/MS spectra of known standards, synthetic compounds, or well-characterized organisms, preferably organized into robust databases. This approach can accommodate different ionization platforms, enabling cross correlations of MS/MS data from ambient ionization, direct infusion, and LC-based methods. Molecular networking not only dereplicates known molecules from complex mixtures, it also captures related analogs, a challenge for many other dereplication strategies. To illustrate its utility as a dereplication tool, we apply mass spectrometry-based molecular networking to a diverse array of marine and terrestrial microbial samples, illustrating the dereplication of 58 molecules including analogs.
The marine environment has been a source of more than 20,000 inspirational natural products discovered over the past 50 years. From these efforts, 9 approved drugs and 12 current clinical trial agents have been discovered, either as natural products or molecules inspired from the natural product structure. To a significant degree, these have come from collections of marine invertebrates largely obtained from shallow water tropical ecosystems. However, there is a growing recognition that marine invertebrates are oftentimes populated with enormous quantities of ‘associated’ or symbiotic microorganisms, and that microorganisms are the true metabolic sources of these most valuable of marine natural products. Also, because of the inherently multidisciplinary nature of this field, a high degree of innovation is characteristic of marine natural product drug discovery efforts.
Tropical parasitic and infectious diseases, such as leishmaniasis, pose enormous global health threats, but are largely neglected in commercial drug discovery programs. However, the Panama International Cooperative Biodiversity Group (ICBG) has been working to identify novel treatments for malaria, Chagas' disease, and leishmaniasis through an investigation of plants and microorganisms from Panama. We have pursued activity-guided isolation from an extract of Lyngbya majuscula that was found to be active against leishmaniasis. A new modified linear peptide from the dragonamide series was isolated, dragonamide E (1), along with two known modified linear peptides, dragonamide A (2) and herbamide B (3). Dragonamides A and E, and herbamide B, exhibited antileishmanial activity with IC 50 values of 6.5, 5.1, and 5.9 µM, respectively. Spectroscopic and stereochemical data for dragonamide E (1) and herbamide B (3; the spectroscopic and stereochemical data for this substance is incomplete in the literature) are presented as well as comparisons of biological activity within the dragonamide compound family. Biosynthetic differences among marine compounds with a terminal free amide are also discussed.Tropical diseases such as leishmaniasis, malaria, and Chagas'disease affect millions of people in equatorial countries each year.1 Inhabitants of these developing-world tropical countries are both at high risk from infection and are often those with the least socio-economic ability to obtain proper treatments; therefore, they are the most likely to develop serious and often fatal illnesses.2 Many tropical diseases have developed resistance to existing therapeutics, thus limiting the effectiveness of these treatments. A majority of the existing agents for treating tropical diseases also have serious side effects that reduce patient compliance with treatment regimens, or in some cases, prohibit any treatment at all. 1 Tropical diseases are largely overlooked in drug discovery programs by major pharmaceutical companies due to the lack of significant financial return on this expensive and time-consuming process (only 13 of the 1,300 *To whom correspondence should be addressed. Tel: +1-858-534-0578. Fax: +1-858-534-0529. wgerwick@ucsd.edu. ║ Current address: Department of Chemistry and Biochemistry, University of California, Santa Cruz. Supporting Information Available: Results and DiscussionL. majuscula was collected using snorkeling in shallow waters from Bocas del Toro, Panama in 2006, and subsequently extracted and fractionated using normal-phase flash chromatography. One of the fractions (60% EtOAc/hexanes) exhibited strong anti-leishmanial activity (7.2% of control parasite growth at 10 µg/mL, experimental detail in Supporting Information) while a second more polar fraction eluting with 100% EtOAc exhibited less potent anti-leishmanial activity (38.2% of control parasite growth at 10 µg/mL). This more polar (100% EtOAc) fraction was successively purified by RP-SPE column chromatography and RP-HPLC, and two compounds w...
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