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Hardt, IH, Jensen PR, Fenical W.  2000.  Neomarinone, and new cytotoxic marinone derivatives, produced by a marine filamentous bacterium (actinomycetales). Tetrahedron Letters. 41:2073-2076.   10.1016/s0040-4039(00)00117-9   AbstractWebsite

Neomarinone (1), a novel metabolite possessing a new sesquiterpene- and polyketide-derived carbon skeleton, and several derivatives, 3-5, of the marinone class of naphthoquinone antibiotics, were isolated from the fermentation broth of a taxonomically-novel marine actinomycete (strain #CNH-099). The structures of the new compounds were determined by comprehensive NMR and mass spectral analyses. Neomarinone (1) and several of the marinone derivatives were shown to be moderately cytotoxic toward human cancer cells in in vitro testing. (C) 2000 Elsevier Science Ltd. All rights reserved.

Haste, NM, Perera VR, Maloney KN, Tran DN, Jensen P, Fenical W, Nizet V, Hensler ME.  2010.  Activity of the streptogramin antibiotic etamycin against methicillin-resistant Staphylococcus aureus. Journal of Antibiotics. 63:219-224.   10.1038/ja.2010.22   AbstractWebsite

The alarming rise of hospital- and community-associated methicillin-resistant Staphylococcus aureus (HA- and CA-MRSA) infections has prompted a desperate search for novel antibiotics. We discovered the streptogramin etamycin produced by an actinomycete species isolated from the coast of Fiji, the first time this antibiotic has been identified from a marine microbe. Etamycin was extracted and purified from this strain (CNS-575) and identified as a three-rotamer species by 2D NMR spectroscopy. Etamycin demonstrated potent activity against HA- and CA-MRSA in microbroth dilution assays, with minimum inhibitory concentrations (MIC) as low as 1-2 mg l(-1) against HA- and CA-MRSA strains. Furthermore, etamycin was also active against other Gram-positive and several Gram-negative pathogens and was found to be non-cytotoxic at concentrations more than 20-fold above MIC. Etamycin displayed favorable time-kill kinetics compared with the first-line MRSA antibiotic, vancomycin, and also conferred significant protection from mortality in a murine model of systemic lethal MRSA infection. These data emphasize the utility of the marine environment as a relatively untapped source of antibiotics against major drug-resistant human pathogens. These studies will also guide future isolation and preclinical development of depsipeptide anti-MRSA compounds from marine-derived actinomycetes. The Journal of Antibiotics (2010) 63, 219-224; doi:10.1038/ja.2010.22; published online 26 March 2010

Haste, NM, Hughes CC, Tran DN, Fenical W, Jensen PR, Nizet V, Hensler ME.  2011.  Pharmacological Properties of the Marine Natural Product Marinopyrrole A against Methicillin-Resistant Staphylococcus aureus. Antimicrobial Agents and Chemotherapy. 55:3305-3312.   10.1128/aac.01211-10   AbstractWebsite

The ongoing spread of methicillin-resistant Staphylococcus aureus (MRSA) strains in hospital and community settings presents a great challenge to public health and illustrates the urgency of discovering new antibiotics. Marinopyrrole A is a member of a structurally novel class of compounds identified from a species of marine-derived streptomycetes with evidence of antistaphylococcal activity. We show that marinopyrrole A has potent concentration-dependent bactericidal activity against clinically relevant hospital-and community-acquired MRSA strains, a prolonged postantibiotic effect superior to that of the current first-line agents vancomycin and linezolid, and a favorable resistance profile. Marinopyrrole A showed limited toxicity to mammalian cell lines (at >20x MIC). However, its antibiotic activity against MRSA was effectively neutralized by 20% human serum. A variety of marinopyrrole analogs were isolated from culture or synthetically produced to try to overcome the inhibitory effect of serum. While many of these compounds retained potent bactericidal effect against MRSA, their activities were also inhibited by serum. Marinopyrrole A has significant affinity for plastic and may therefore have potential as a potent anti-MRSA agent in cutaneous, intracatheter, or antibiotic-lock applications.

Haste, NM, Thienphrapa W, Tran DN, Loesgen S, Sun P, Nam SJ, Jensen PR, Fenical W, Sakoulas G, Nizet V, Hensler ME.  2012.  Activity of the thiopeptide antibiotic nosiheptide against contemporary strains of methicillin-resistant Staphylococcus aureus. Journal of Antibiotics. 65:593-598.   10.1038/ja.2012.77   AbstractWebsite

The rapid rise in antimicrobial resistance in bacteria has generated an increased demand for the development of novel therapies to treat contemporary infections, especially those caused by methicillin-resistant Staphylococcus aureus (MRSA). However, antimicrobial development has been largely abandoned by the pharmaceutical industry. We recently isolated the previously described thiopeptide antibiotic nosiheptide from a marine actinomycete strain and evaluated its activity against contemporary clinically relevant bacterial pathogens. Nosiheptide exhibited extremely potent activity against all contemporary MRSA strains tested including multiple drug-resistant clinical isolates, with MIC values <= 0.25 mg l(-1). Nosiheptide was also highly active against Enterococcus spp. and the contemporary hypervirulent BI/NAP1/027 strain of Clostridium difficile but was inactive against most Gram-negative strains tested. Time-kill analysis revealed nosiheptide to be rapidly bactericidal against MRSA in a concentration- and time-dependent manner, with a nearly 2-log kill noted at 6 h at 10 x MIC. Furthermore, nosiheptide was found to be non-cytotoxic against mammalian cells at >>100 x MIC, and its anti-MRSA activity was not inhibited by 20% human serum. Notably, nosiheptide exhibited a significantly prolonged post-antibiotic effect against both healthcare- and community-associated MRSA compared with vancomycin. Nosiheptide also demonstrated in vivo activity in a murine model of MRSA infection, and therefore represents a promising antibiotic for the treatment of serious infections caused by contemporary strains of MRSA. The Journal of Antibiotics (2012) 65, 593-598; doi:10.1038/ja.2012.77; published online 10 October 2012

Hughes, CC, MacMillan JB, Gaudencio SR, Jensen PR, Fenical W.  2009.  The Ammosamides: Structures of Cell Cycle Modulators from a Marine-Derived Streptomyces Species. Angewandte Chemie-International Edition. 48:725-727.   10.1002/anie.200804890   Website
Hughes, CC, Kauffman CA, Jensen PR, Fenical W.  2010.  Structures, Reactivities, and Antibiotic Properties of the Marinopyrroles A-F. Journal of Organic Chemistry. 75:3240-3250.   10.1021/jo1002054   AbstractWebsite

Cultivation of actinomycete strain CNQ-418, retrieved from a deep ocean sediment sample off the coast of La Jolla, CA, has provided marinopyrroles A F. Sharing just 98% 16S rRNA gene sequence identity with S. sannurensis, the strain likely represents a new Streptomyces species. The metabolites contain an unusual 1,3'-bipyrrole core decorated with several chlorine and bromine substituents and possess marked antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). The congested N,C-biaryl bond establishes an axis of chirality that, for marinopyrroles A-E, is configurationally stable at room temperature. Moreover, the natural products are fashioned strictly in the M-configuration. The Paal-Knorr condensation was adapted for the synthesis of the 1,3'-bipyrrole core. Halogenation of this material with N-bromosuccinimide cleanly furnished the 4,4',5,5'-tetrahalogenated core that characterizes this class of marine-derived metabolites.

Hughes, CC, Prieto-Davo A, Jensen PR, Fenical W.  2008.  The marinopyrroles, antibiotics of an unprecedented structure class from a marine Streptomyces sp. Organic Letters. 10:629-631.   10.1021/ol702952n   AbstractWebsite

Cultivation of an obligate marine Streptomyces strain has furnished the marinopyrroles A and B, densely halogenated, axially chiral metabolites that contain an uncommon bispyrrole structure. X-ray analysis of marinopyrrole B showed that the natural product exists as an atropoenantiomer with the M-configuration. Though configurationally stable at room temperature, M(-)-marinopyrrole A can be racemized at elevated temperatures to yield the non-natural P-(+)-atropo-enantiomer. The marinopyrroles possess potent antibiotic activities against methicillin-resistant Staphylococcus aureus.