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and activity of biomimetic biofilm disruptors

Activity of Biomimetic Biofilm Disruptors ..

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Synthesis and activity of biomimetic biofilm disruptors.

A bacterial symbiont is converted from an inedible producer of beneficial molecules into a food by a single mutation in the gacA gene. (2013)

Synthesis and activity of biomimetic biofilm disruptors. (2013)

A bacterial sulfonolipid triggers multicellular development in the closest living relatives of animals. (2012)

Small molecule perimeter defense in entomopathogenic bacteria. (2012)

Liver-stage malaria parasites vulnerable to diverse chemical scaffolds. (2012)

A self-produced trigger for biofilm disassembly that targets exopolysaccharide. (2012)

Roseobacticides: small molecule modulators of an algal-bacterial symbiosis. (2011)

The Jekyll-and-Hyde chemistry of Phaeobacter gallaeciensis. (2011)

Bacterial protection of beetle-fungus mutualism. (2008)

The evolution of gene collectives: How natural selection drives chemical innovation. (2008)

Lessons from natural molecules. (2004)

and Yiying Wu — 2923–2926 Synthesis and Activity of Biomimetic Biofilm Disruptors Thomas ..

Exogenous agmatine restored biofilm formation to the ΔspeA strain, whereas putrescine did not (, A and B). Agmatine is the product of SpeA activity and precursor to putrescine biosynthesis in B. subtilis (B). The SpeB, SpeD, and SpeE enzymes of B. subtilis convert agmatine to putrescine and then spermidine (B and A) (, ). It is surprising therefore that exogenous putrescine could not restore biofilm formation to the ΔspeA strain (A). To determine whether putrescine was converted to spermidine in the ΔspeA strain, the strain was grown in liquid MSgg containing 500 μ putrescine, agmatine, or neither (B). Analysis of polyamine content of the cells by HPLC revealed that no spermidine is produced from exogenous putrescine, whereas it is produced from exogenous agmatine. Although the cells were washed four times with fresh polyamine-free MSgg growth medium before extraction of intracellular polyamines with trichloroacetic acid, a large peak of putrescine was present when ΔspeA cells had been grown in exogenous putrescine. With Gram-negative bacteria, such washing is sufficient to remove externally bound polyamine, but it is feasible that the thicker envelope of Gram-positive bacteria may bind polyamines more avidly. Alternatively, putrescine may be taken up but for whatever reason not converted to spermidine. It is significant that B. subtilis does not encode homologues of either the E. coli potABCD spermidine-preferential uptake transporter or the potFGHI putrescine-specific uptake transporter.

Synthesis and activity of biomimetic biofilm disruptors JACS ..

and activity of biomimetic biofilm disruptors.

We have also demonstrated that production of cahuitamycins A–C is specified by a convergent pathway specified by the cah biosynthetic gene cluster comprised of two unlinked genetic loci. The inherently flexible starter unit adenylating enzyme CahJ was exploited to produce two additional analogues in the engineered ΔcahI strain DHS334. The new cahuitamycin D analogue displays twofold-enhanced biofilm inhibitory activity compared with the cahuitamycin C natural product. These results establish a unique opportunity for developing and discovering new antibiotics from genetically engineered strains bearing inherent flexibility in pathway initiation processes. More importantly, given the simultaneous decline in antibiotic drug discovery and increased incidence of multidrug resistant bacteria, the cahuitamycins may represent a propitious starting point for discovery and development of new therapeutics against dangerous human pathogens involving biofilm formation.

The application of the streptomycin resistance-mediated screening of the Streptomyces strain identified from HTS against A. baumannii has yielded a novel structural class of biofilm inhibitors derived from a marine microbial NPE library. Cahuitamycins A–E (15) inhibit the ability of A. baumannii to generate a biofilm, which is involved in the emergence of a widespread antibiotic resistance phenotype,. The cahuitamycins are most active in apo form, with chelation of FeIII over time resulting in attenuated biological activity. The cahuitamycins along with allied chemical entities with distinct biological activity provides a primary foundation for future medicinal chemistry and synthetic exploration towards the development of an efficacious drug to prevent or limit biofilm formation.

Staphylococcus aureus Infections — NEJM

02/08/2014 · Synthesis and activity of biomimetic biofilm disruptors Looking for good argument paper ideas

The two main transcriptome responses in the ΔspeD strain concern metabolism and production of the biofilm matrix. Relative to the wild-type strain, the ΔspeD strain has down-regulated pathways involved in purine catabolism, methionine salvage, and methionine and nitrogen starvation responses. These responses are part of the PucR, TnrA, and S-box regulons. Elimination of S-adenosylmethionine decarboxylase (SpeD) activity blocks flux of methionine and nitrogen into spermidine via S-adenosylmethionine. The transcriptome responses suggest that the cell senses excess S-adenosylmethionine, methionine, and nitrogen generally. Furthermore, the methionine salvage pathway that rescues methionine and the purine component from methylthioadenosine generated by spermidine biosynthesis is down-regulated. This may contribute also to the purine catabolism/uptake response, which down-regulates enzymes and transporters involved in salvaging purines and nitrogen. Although this metabolic response to a presumed methionine/S-adenosylmethionine excess is unsurprising, it is an interesting insight into the extent of nitrogen flux through these metabolites into spermidine. Two unrelated genes affecting membrane fluidity were repressed in ΔspeD, the liaIH operon, encoding membrane anchor and phage shock protein A paralogue, and the des gene encoding a phospholipid desaturase whose expression increases membrane fluidity () and is induced at low temperatures. The phage shock protein A paralogue LiaH is produced in response to cell envelope perturbations and is located in the membrane (). Repression of liaHI and des expression suggests that the membrane of the ΔspeD strain may be sensed by the cell as being too fluid.

A very small effect was detectable with norspermine and spermine but only in the ΔspeA and not the ΔspeD strain. These results confirm that only norspermidine can replace the role of spermidine in robust biofilm formation (, ). Norspermidine contains only aminopropyl moieties, and homospermidine only aminobutyl moieties, suggesting that the aminopropyl side of spermidine may be the active part of the structure for biofilm formation. To test this hypothesis, synthetic C-methylated analogues (C) of spermidine were tested (at 100 μ) to determine whether they were able to replace spermidine for biofilm formation (B). All C-methylated spermidine analogues were able to generate complexity (biofilm wrinkliness and three dimensionality) in biofilm formation in the ΔspeA strain but much less so in the ΔspeD strain. Furthermore, the 1- and 2-methylspermidine analogues were less effective than the 3- and 8-methylspermidine analogues, indicating that C-methylation on the aminopropyl side is more deleterious than on the aminobutyl side.

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A self-produced trigger for biofilm disassembly that ..

Ubiquitous polyamine spermidine is not required for normal planktonic growth of Bacillus subtilis but is essential for robust biofilm formation. However, the structural features of spermidine required for B. subtilis biofilm formation are unknown and so are the molecular mechanisms of spermidine-stimulated biofilm development. We report here that in a spermidine-deficient B. subtilis mutant, the structural analogue norspermidine, but not homospermidine, restored biofilm formation. Intracellular biosynthesis of another spermidine analogue, aminopropylcadaverine, from exogenously supplied homoagmatine also restored biofilm formation. The differential ability of C-methylated spermidine analogues to functionally replace spermidine in biofilm formation indicated that the aminopropyl moiety of spermidine is more sensitive to C-methylation, which it is essential for biofilm formation, but that the length and symmetry of the molecule is not critical. Transcriptomic analysis of a spermidine-depleted B. subtilis speD mutant uncovered a nitrogen-, methionine-, and S-adenosylmethionine-sufficiency response, resulting in repression of gene expression related to purine catabolism, methionine and S-adenosylmethionine biosynthesis and methionine salvage, and signs of altered membrane status. Consistent with the spermidine requirement in biofilm formation, single-cell analysis of this mutant indicated reduced expression of the operons for production of the exopolysaccharide and TasA protein biofilm matrix components and SinR antagonist slrR. Deletion of sinR or ectopic expression of slrR in the spermidine-deficient ΔspeD background restored biofilm formation, indicating that spermidine is required for expression of the biofilm regulator slrR. Our results indicate that spermidine functions in biofilm development by activating transcription of the biofilm matrix exopolysaccharide and TasA operons through the regulator slrR.

Harvard University Center for the Environment

Following initial identification of the active principles, regrowth of the wild-type S. gandocaensis over several months showed complete loss of production of the active biofilm inhibitor molecules. Therefore, we decided to immediately pursue a ribosome engineering approach to restore and improve production of the active metabolites. This approach has been employed for activation of secondary metabolite production in Streptomyces spp., and can result in significantly enhanced yields by inducing point mutations in ribosomal protein-encoding genes (for example, rpsL). Several rounds of mutagenesis based on a streptomycin resistance phenotype resulted in an improved strain DHS287 of S. gandocaensis (; ), a fourth-generation mutant with restored stable production that generates several-fold increased quantities of active molecules compared with initial wild-type levels. Genetic analysis revealed that the streptomycin-induced ribosome engineering introduced a point mutation in the rpsL gene, which encodes the ribosomal protein S12, in the engineered strain (; ). Previous studies have shown that mutations in the S12 gene render cells potentially more active for polypeptide synthesis under typical starvation conditions during the late growth phase. This effort appears to be the first reported instance where complete loss of an active, but structurally uncharacterized natural product has been recovered using the ribosome engineering approach.

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