Production of Ramoplanin and Ramoplanin Analogs by Actinomycetes.

Ramoplanin is a glycolipodepsipeptide antibiotic obtained from fermentation of sp. ATCC 33076 that exhibits activity against clinically important multi-drug-resistant, Gram-positive pathogens including vancomycin-resistant (VRE), methicillin-resistant (MRSA), and vancomycin-intermediate resistant . It disrupts bacterial cell wall through a unique mechanism of action by sequestering the peptidoglycan intermediate Lipid II and therefore does not show cross-resistance with other antibiotics.

Analysis of cytotoxic activity at short incubation times reveals profound differences among Annonaceus acetogenins, inhibitors of mitochondrial Complex I.

Annonaceous acetogenins are potent cytotoxic agents against tumor cell lines as well as potent inhibitors of mitochondrial Complex I (Degli Esposti and Ghelli Biochim Biophys Acta 1187:116-120, 1994; Degli Esposti et al. Biochem J 301(Pt 1):161-167, 1994; Tormo et al. Arch Biochem Biophys 369:119-126, 1999).

Mitochondrial complex I inhibitors, acetogenins, induce HepG2 cell death through the induction of the complete apoptotic mitochondrial pathway.

The development of new anti-neoplastic drugs is a key issue for cancer chemotherapy due to the reality that, most likely, certain cancer cells are resistant to current chemotherapy. The past two decades have witnessed tremendous advances in our understanding of the pathogenesis of cancer. These advances have allowed identification new targets as oncogenes, tumor supressor genes and the possible implication of the mitochondria (Fulda et al.

Territorial Polemics: A Response to Roberts.

Our recent paper Lledo-Ferrer et al. (International Journal of Primatology 32: 974-991, 2011) questioned the classic view of territoriality and chemical communication in wild callitrichids, saddleback tamarins (Saguinus fuscicollis). We suggested that rather than defending a territory or resources, chemical communication was more likely to be a way of exchanging reproductive information between groups.

The Equivocal Relationship Between Territoriality and Scent Marking in Wild Saddleback Tamarins (Saguinus fuscicollis).

Researchers have often assumed that scent marking serves a territorial function in callitrichines, although some controversy exists. To fulfill such a function, scent marks should 1) prevent intrusions, 2) ensure access to feeding resources, 3) enable avoidance of intergroup encounters, or 4) play an important role in the aggressive encounters between groups. We studied 13 saddleback tamarins (Saguinus fuscicollis) belonging to 3 free-ranging groups, which formed mixed-species troops with moustached tamarins (S.

Can overmarking be considered as a means of chemical mate guarding in a wild callitrichid?

Mate guarding is a male strategy to monopolize matings and thus to ensure paternity. Since in callitrichids female reproductive status is advertised by scent marks, one may expect mate guarding by chemical means. We addressed this question during an episode of consortship observed in a polyandrous trio of wild saddleback tamarins (Saguinus fuscicollis).

Discovery of the parnafungins, antifungal metabolites that inhibit mRNA polyadenylation, from the Fusarium larvarum complex and other Hypocrealean fungi.

Evaluation of fungal fermentation extracts with whole cell Candida albicans activity resulted in the identification of a novel class of isoxazolidinone-containing metabolites named parnafungins. Chemical-genetic profiling with the C. albicans fitness test identified the biochemical target as inhibition of polyadenosine polymerase, a component of the mRNA cleavage and polyadenylation complex.

Reconciliation in captive cotton-top tamarins (Saguinus oedipus), a cooperative breeding primate.

Reconciliation has been demonstrated in all primate species in which the phenomenon has been studied. However, reconciliation has been studied in only two species of callitrichids, and conclusions remain controversial. The first aim of this study has been to find out whether captive cotton-top tamarins (Saguinus oedipus) reconcile, since this is the first such study on this species.

Distribution of the antifungal agents sordarins across filamentous fungi.

Sordarins are a class of natural antifungal agents which act by specifically inhibiting fungal protein synthesis through their interaction with the elongation factor 2, EF2. A number of natural sordarins produced by diverse fungi of different classes have been reported in the literature. We have run an exhaustive search of sordarin-producing fungi using two different approaches consecutively, the first one being a differential sensitivity screen using a sordarin-resistant mutant yeast strain run in parallel with a wild type strain, and the second one an empiric screen against Candida albicans followed by early detection of sordarins by LC-MS analysis.

Antisense-guided isolation and structure elucidation of pannomycin, a substituted cis-decalin from Geomyces pannorum.

Antisense-based screening strategies can be used to sensitize a microorganism and selectively detect inhibitors against a particular cellular target of interest. A strain of Staphylococcus aureus that generates an antisense RNA against SecA,a central member of the protein secretion machinery, has been used to screen for novel antibacterials. Possible inhibitors of the SecA ATP-ase were selected with a high-throughput, two-plate agar-based whole cell differential sensitivity screen.

Changes in body mass of expectant male cotton-top tamarins (Saguinus oedipus).

It has been noted that expectant cotton-top tamarin males in captivity experience a body mass increase during the last months of their mates' pregnancies, and this has been explained as being a male physiological response. We studied the body mass of 4 inexperienced and 4 experienced expectant males, and we expected to observe a larger body mass increase among the experienced ones since they undergo multiple hormonal changes in comparison to inexperienced expectant males. However, while inexperienced expectant males gained body mass during months 4-6 of the pregnancy period by a mean +/-SD of 5.

Development of an HTS assay for the search of anti-influenza agents targeting the interaction of viral RNA with the NS1 protein.

The NS1 protein is a nonstructural protein encoded by the influenza A virus. It is responsible for many alterations produced in the cellular metabolism upon infection by the virus and for modulation of virus virulence. The NS1 protein is able to perform a large variety of functions due to its ability to bind various types of RNA molecules, from both viral and nonviral origin, and to interact with several cell factors.

Isolation and structure elucidation of parnafungins, antifungal natural products that inhibit mRNA polyadenylation.

The Candida albicans Fitness Test, a whole-cell screening platform, was used to profile crude fermentation extracts for novel antifungal natural products with interesting mechanisms of action. An extract with intrinsic antifungal activity from the fungus Fusarium larvarum displayed a Fitness Test profile that strongly implicated mRNA processing as the molecular target responsible for inhibition of fungal growth. Isolation of the active components from this sample identified a novel class of isoxazolidinone-containing natural products, which we have named parnafungins.

PAP inhibitor with in vivo efficacy identified by Candida albicans genetic profiling of natural products.

Natural products provide an unparalleled source of chemical scaffolds with diverse biological activities and have profoundly impacted antimicrobial drug discovery. To further explore the full potential of their chemical diversity, we survey natural products for antifungal, target-specific inhibitors by using a chemical-genetic approach adapted to the human fungal pathogen Candida albicans and demonstrate that natural-product fermentation extracts can be mechanistically annotated according to heterozygote strain responses. Applying this approach, we report the discovery and characterization of a natural product, parnafungin, which we demonstrate, by both biochemical and genetic means, to inhibit poly(A) polymerase.

Biodiversity, chemical diversity and drug discovery.

Drugs developed from microbial natural products are in the fundaments of modern pharmaceutical companies. Despite decades of research, all evidences suggest that there must remain many interesting natural molecules with potential therapeutic application yet to be discovered. Any efforts to successfully exploit the chemical diversity of microbial secondary metabolites need to rely heavily on a good understanding of microbial diversity, being the working hypothesis that maximizing biological diversity is the key strategy to maximizing chemical diversity.

Molecular phylogenetic studies show Omphalina giovanellae represents a new section of Clitopilus (Agaricomycetes).

After reconsidering the specific characters of Omphalia giovanellae and applying data from the sequences of the D1-D2 domain of the 28S rRNA gene and the ITS region of material collected in Italy and Spain, the species is ascribed to the genus Clitopilus. Considering the rather peculiar characters, especially the smooth spores, C. giovanellae is ascribed to the new section Omphaloidei sect.

Discovery of platencin, a dual FabF and FabH inhibitor with in vivo antibiotic properties.

Emergence of bacterial resistance is a major issue for all classes of antibiotics; therefore, the identification of new classes is critically needed. Recently we reported the discovery of platensimycin by screening natural product extracts using a target-based whole-cell strategy with antisense silencing technology in concert with cell free biochemical validations. Continued screening efforts led to the discovery of platencin, a novel natural product that is chemically and biologically related but different from platensimycin.

Identification of diverse microbial metabolites as potent inhibitors of HIV-1 Tat transactivation.

HIV-1 Tat is one of six regulatory proteins that are required for viral replication and is an attractive target for the development of new anti-HIV agents. Screening of microbial extracts using a whole cell Tat-dependent transactivation assay, which guided the separation of the active broths, led to the identification of five structurally diverse classes (M(R) range 232-1126) of natural products. These include i) three sesquiterpenoids, namely, sporogen-AO1, petasol, and 6-dehydropetasol, ii) two resorcylic 14-membered lactones, namely monorden and monocillin IV, iii) a ten-membered lactone, iv) a quinoline and quinoxiline bicyclic octadepsipeptides, namely echinomycin and UK-63598, and v) a cyclic heptapeptide, ternatin.

Studies on Morinia: recognition of Morinia longiappendiculata sp. nov. as a new endophytic fungus, and a new circumscription of Morinia pestalozzioides.

A new coelomycete, Morinia longiappendiculata sp. nov., isolated from living stems of four plant species in central Spain, is described.

Isolation, structure, and absolute stereochemistry of platensimycin, a broad spectrum antibiotic discovered using an antisense differential sensitivity strategy.

Fatty acids are essential for survival of bacteria and are synthesized by a series of enzymes including the elongation enzymes, beta-ketoacyl acyl carrier protein synthase I/II (FabF/B). Inhibition of fatty acid synthesis is one of the new targets for the discovery and development of antibacterial agents. Platensimycin (1a) is a novel broad spectrum Gram-positive antibiotic produced by Streptomyces platensis.

Automated agar plate streaker: a linear plater on Society for Biomolecular Sciences standard plates.

Several protocols for bacterial isolation and techniques for aerobic plate counting rely on the use of a spiral plater to deposit concentration gradients of microbial suspensions onto a circular agar plate to isolate colony growth. The advantage of applying a gradient of concentrations across the agar surface is that the original microbiological sample can be applied at a single concentration rather than as multiple serial dilutions. The spiral plater gradually dilutes the sample across a compact area and therefore saves time preparing dilutions and multiple agar plates.

Platensimycin is a selective FabF inhibitor with potent antibiotic properties.

Bacterial infection remains a serious threat to human lives because of emerging resistance to existing antibiotics. Although the scientific community has avidly pursued the discovery of new antibiotics that interact with new targets, these efforts have met with limited success since the early 1960s. Here we report the discovery of platensimycin, a previously unknown class of antibiotics produced by Streptomyces platensis.

Highly substituted terphenyls as inhibitors of parasite cGMP-dependent protein kinase activity.

Parasite cGMP-dependent protein kinase (PKG) is one of the validated biochemical targets for the treatment of coccidiosis. We screened our library of natural product extracts for inhibitors of parasite PKG for the discovery of anticoccidial leads. Terferol (1) and three new terphenyls (2, 3, and 4) were isolated using bioassay-guided fractionation of the microbial extract of a Phoma sp.