We report the activation of a PTM gene cluster in marine-derived Streptomyces pactum, leading to the discovery of six new PTMs, the pactamides A-F.

Polycyclic tetramate macrolactams (PTMs), a widely distributed class of structurally complex natural products exhibiting diverse biological activities, share a tetramate-containing macrocyclic lactam ring fused to a subset of carbocyclic rings. More than 30 naturally occurring PTM members have been reported. Representative members include ikarugamycin, HSAF, and alteramides. The emerging significance of PTMs in medicinal applications has raised attentions on their biosynthetic studies. These studies have unveiled the unexpected conservation of compact PTM biosynthetic loci in phylogenetically diverse bacteria and elucidated mechanisms for key steps in PTM biosynthesis. PTMs were demonstrated to be derived from the common origin of a hybrid polyketide synthase (PKS)/nonribosomal peptide synthetase (NRPS) pathway, in which the PKS portion was iteratively used to generate two separate polyketide chains. A common tetramate-containing polyene intermediate was proposed to be the final product of all PTM PKS/NRPS assembly lines. Subsequently, a set of oxidoreductases acted in a not yet clearly understood way to dictate the manner of cyclizations to yield different polycycle ring systems in PTMs. The only well studied example was the formation of the inner fivemembered ring in ikarugamycin, which was catalyzed by an alcohol dehydrogenase via a [1 + 6] Michael addition. Nonetheless, these studies have illustrated the extraordinary simplicity of nature's art in the biosynthesis of PTMs with complex structures and paved the way to further expand the structural diversity of the family of medicinally relevant PTMs by genome mining and combinatorial biosynthesis.

In 2004, following a cluster of kala-azar cases in Chatrakhali, West Bengal, India, we screened and treated this endemic village for leishmaniasis infection. In 2005, following new reports of kala-azar, we screened the village again and conducted a retrospective cohort study (exposure period: August 2004 to July 2005). We defined an incident case of leishmaniasis as a new seropositive sample (>or=1:1600 dilution in a direct agglutination test) in a person seronegative in 2004. We obtained information about potential risk factors and calculated the relative risk (RR) of infection for exposure to these factors. One hundred and fifty (20%) of the 751 residents acquired leishmaniasis in 1 year. Factors associated with infection included residing in homes with mud walls (RR 4.3), dampness in the home (RR 2.5), proximity to bodies of water (RR 2.5) and livestock ownership (RR 2.4). Sleeping dressed (RR 0.4), or under a bed net (RR 0.5) or in a cot (RR 0.6) were associated with a lower risk. High rates of infection indicated that transmission persisted in this community. Poor housing conditions were associated with a higher risk, while personal protection measures against vectors were effective. Major housing improvement and personal protection efforts are needed to protect this vulnerable population from leishmaniasis.

We conducted global genome mining of 162,672 bacterial genomes and identified 829 cyclodipeptide (CDP) biosynthesis gene clusters (BGC) containing a cytochrome P450 gene. Heterologous expression of BGC from Saccharopolyspora hirsuta DSM 44795 led to the identification of two novel crownlike CDPs, cyctetryptomycin A (4) and B (5), which possess unprecedented complex macrocycle and show neuroprotective activity. The two cytochrome P450s found in the BGC catalyze sequential reactions leading to the cyclization of diketopiperazine dimers.

Xylitol is a white crystalline, amorphous sugar alcohol and low-calorie sweetener. Xylitol prevents demineralization of teeth and bones, otitis media infection, respiratory tract infections, inflammation and cancer progression. NADPH generated in xylitol metabolism aid in the treatment of glucose-6-phosphate deficiency-associated hemolytic anemia. Moreover, it has a negligible effect on blood glucose and plasma insulin levels due to its unique metabolism. Its diverse applications in pharmaceuticals, cosmetics, food and polymer industries fueled its market growth and made it one of the top 12 bio-products. Recently, xylitol has also been used as a drug carrier due to its high permeability and non-toxic nature. However, it become a challenge to fulfil the rapidly increasing market demand of xylitol. Xylitol is present in fruit and vegetables, but at very low concentrations, which is not adequate to satisfy the consumer demand. With the passage of time, other methods including chemical catalysis, microbial and enzymatic biotransformation, have also been developed for its large-scale production. Nevertheless, large scale production still suffers from high cost of production. In this review, we summarize some alternative approaches and recent advancements that significantly improve the yield and lower the cost of production.

In rural West Bengal, outbreaks of cholera are often centred around ponds that is a feature of the environment. Five investigations of laboratory-confirmed, pond-centred outbreaks of cholera were reviewed. Case-control odds ratios were approximated with relative risks (RRs) as the incidence was low. The environment was investigated to understand how the pond(s) could have become contaminated and could have infected villagers. The five outbreaks of cholera in 2004-2008 led to 277 cases and three deaths (median attack rate: 51/1,000 people; case fatality: 1.1%; median age of case-patients: 22 years; median duration: 13 days, range: 6-15 days). Factors significantly (p<0.05) associated with cholera in the case-control (n=4) and cohort investigations (n=1) included washing utensils in ponds (4 outbreaks of cholera, RR range: 6-12), bathing (3 outbreaks of cholera, RR range: 3.5-9.3), and exposure to pond water, including drinking (2 outbreaks of cholera, RR range: 2.1-3.2), mouth washing (1 outbreak of cholera, RR: 4.8), and cooking (1 outbreak of cholera, RR: 3.0). Initial case-patients contaminated ponds through washing soiled clothes (n=4) or defaecation (n=1). Ubiquitous ponds used for many purposes transmit cholera in West Bengal. Focused health education, hygiene, and sanitation must protect villagers, particularly following the occurrence of an index case in a village that has ponds.

A mononuclear cobalt(III) complex [Co(bpy) 2 Cl 2 ]NO 3 •2H 2 O (1) (bpy = 2,2-bipyridine) has been synthesized and crystallographically characterized. Self-assembly of the lattice water molecules from rectangular tetrameric water cluster interacts with nitrate anion along the c-axis forming a six membered hexagonal water-nitrate cluster. It presents a new mode of association of water molecules with nitrate molecules which is not predicted theoretically or found experimentally. The molecule effectively cleaves bacterial genomic DNA and shows important cytotoxicity against human hepatocarcinoma cell (HepG2).

Streptomyces are among the most promising genera in terms of production ability to biosynthesize a variety of bioactive secondary metabolites with pharmaceutical interest. Coinciding with the increase in genomic sequencing of these bacteria, mining of their genomes for biosynthetic gene clusters (BGCs) has become a routine component of natural product discovery. Herein, we describe the isolation and characterization of a Streptomyces tendae VITAKN with quorum sensing inhibitory (QSI) activity that was isolated from southern coastal part of India. The nearly complete genome consists of 8,621,231bp with a GC content of 72.2%. Sequence similarity networks of the BGCs detected from this strain against the Minimum Information about a Biosynthetic Gene Cluster (MIBiG) database and 3365 BGCs predicted by antiSMASH analysis of publicly available complete Streptomyces genomes were generated through the BiG-SCAPE-CORASON platform to evaluate its biosynthetic novelty. Crude extract analysis using high-performance liquid chromatography connected to high resolution tandem mass spectrometry (HPLC-HRMS/MS) and dereplication through the Global Natural Product Social Molecular Networking (GNPS) online workflow resulted in the identification of cyclic dipeptides (2, 5-diketopiperazines, DKPs) in the extract, which are known to possess QSI activity. Our results highlight the potential of genome mining coupled with LC-HRMS/MS and in silico tools (GNPS) as a valid approach for the discovery of novel QSI lead compounds. This study also provides the biosynthetic diversity of BGCs and an assessment of the predicted chemical space yet to be discovered.