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.