Designer broad-spectrum polyimidazolium antibiotics

For a myriad of different reasons most antimicrobial peptides (AMPs) have failed to reach clinical application. Different AMPs have different shortcomings including but not limited to toxicity issues, potency, limited spectrum of activity, or reduced activity in situ. We synthesized several cationic peptide mimics, main-chain cationic polyimidazoliums (PIMs), and discovered that, although select PIMs show little acute mammalian cell toxicity, they are potent broad-spectrum antibiotics with activity against even pan-antibiotic-resistant gram-positive and gram-negative bacteria, and mycobacteria. We selected PIM1, a particularly potent PIM, for mechanistic studies. Our experiments indicate PIM1 binds bacterial cell membranes by hydrophobic and electrostatic interactions, enters cells, and ultimately kills bacteria. Unlike cationic AMPs, such as colistin (CST), PIM1 does not permeabilize cell membranes. We show that a membrane electric potential is required for PIM1 activity. In laboratory evolution experiments with the gram-positive Staphylococcus aureus we obtained PIM1-resistant isolates most of which had menaquinone mutations, and we found that a site-directed menaquinone mutation also conferred PIM1 resistance. In similar experiments with the gram-negative pathogen Pseudomonas aeruginosa, PIM1-resistant mutants did not emerge. Although PIM1 was efficacious as a topical agent, intraperitoneal administration of PIM1 in mice showed some toxicity. We synthesized a PIM1 derivative, PIM1D, which is less hydrophobic than PIM1. PIM1D did not show evidence of toxicity but retained antibacterial activity and showed efficacy in murine sepsis infections. Our evidence indicates the PIMs have potential as candidates for development of new drugs for treatment of pan-resistant bacterial infections.

AMPs and AMP mimics have attracted considerable attention as candidates for therapeutic development (1). The basic design elements include a region of charged residues, generally cationic residues, enabling interaction with bacterial cell surfaces, combined with a hydrophobic nature in AMPs (2). Unfortunately, AMPs and related polymers, in general, have one or more issues that limit their use as broad-spectrum antibiotics. Some are quite toxic to human cells, the potency of some is not adequate for human administration, others are sensitive to salt at levels present in human fluids, and some are too difficult and expensive to synthesize (3, 4). One broad-spectrum antimicrobial peptide, CST has seen increased recent use as a last resort antibiotic. CST is believed to kill bacteria by virtue of its ability to disrupt membrane integrity (5). This antibiotic requires intravenous administration and is nephrotoxic (6). The emergence of CST-resistant pathogens has also become a significant problem (7). We are unaware of any new broad-spectrum AMPs that have advanced to clinical trials.Imidazolium (IM) salts are antimicrobials (8), and there is an emerging literature on antimicrobial activity of side-chain and main-chain polyimidazolium (PIM) salts with chemical structures that are in some ways similar to those we describe. Although PIMs are potent antimicrobials, there are biocompatibility problems hindering their development, and some have somewhat limited activity spectra. As with other AMPs, there have been toxicity issues, potency issues, and delivery issues as many have large molecular masses, and there is little known about mammalian cell toxicity or mechanism of action (9–12).Here we show that members of a series of PIMs we designed and synthesized are potent broad-spectrum antibacterial compounds. We selected two for further analysis and showed they retain activity even against pan-antibiotic-resistant bacteria. Unlike CST and many other AMPs, which disrupt bacterial membranes, our model PIM is bactericidal without disrupting bacterial membranes. Our experiments provide insights about mechanism of action, the potential for the emergence of PIM resistance, and indicate PIMs are effective against a model gram-negative and a model gram-positive pathogen in murine infection models.     

Probability Mapping to Determine the Spatial Risk Pattern of Acute Gastroenteritis in Coimbatore District,India, Using Geographic Information Systems (GIS)

Background:

Maps show well the spatial configuration of information. Considerable effort is devoted to the development of geographical information systems (GIS) that increase understanding of public health problems and in particular to collaborate efforts among clinicians, epidemiologists, ecologists, and geographers to map and forecast disease risk.

Objectives:

Small populations tend to give rise to the most extreme disease rates, even if the actual rates are similar across the areas. Such situations will follow the decision-maker''s attention on these areas when they scrutinize the map for decision making or resource allocation. As an alternative, maps can be prepared using P-values (probabilistic values).

Materials and Methods:

The statistical significance of rates rather than the rates themselves are used to map the results. The incidence rates calculated for each village from 2000 to 2009 is used to estimate λ, the expected number of cases in the study area. The obtained results are mapped using Arc GIS 10.0.

Results:

The likelihood of infections from low to high is depicted in the map and it is observed that five villages namely, Odanthurai, Coimbatore Corporation, Ikkaraiboluvampatti, Puliakulam, and Pollachi Corporation are more likely to have significantly high incidences.

Conclusion:

In the probability map, some of the areas with exceptionally high or low rates disappear. These are typically small unpopulated areas, whose rates are unstable due to the small numbers problem. The probability map shows more specific regions of relative risks and expected outcomes.     

Eco-friendly microbial route to synthesize cobalt nanoparticles using Bacillus thuringiensis against malaria and dengue vectors

The developments of resistance and persistence to chemical insecticides and concerns about the non-target effects have prompted the development of eco-friendly mosquito control agents. The aim of this study was to investigate the larvicidal activities of synthesized cobalt nanoparticles (Co NPs) using bio control agent, Bacillus thuringiensis against malaria vector, Anopheles subpictus and dengue vector, Aedes aegypti (Diptera: Culicidae). The synthesized Co NPs were characterized by X-ray diffraction (XRD), Fourier transform infrared (FTIR), Field-emission scanning electron microscopy (FESEM) with energy dispersive X-ray spectroscopy, and Transmission electron microscopy (TEM). XRD analysis showed three distinct diffraction peaks at 27.03°, 31.00°, and 45.58° indexed to the planes 102, 122, and 024, respectively on the face-centered cubic cobalt acetate with an average size of 85.3 nm. FTIR spectra implicated role of the peak at 3,436 cm^?1 for O–H hydroxyl group, 2924 cm^?1 for methylene C–H stretch in the formation of Co NPs. FESEM analysis showed the topological and morphological appearance of NPs which were found to be spherical and oval in shape. TEM analysis showed polydispersed and clustered NPs with an average size of 84.81 nm. The maximum larvicidal mortality was observed in the cobalt acetate solution, B. thuringiensis formulation, and synthesized Co NPs against fourth instar larvae of A. subpictus and A. aegypti with LC₅₀ values of 29.16, 8.12, 3.59 mg/L; 34.61, 6.94, and 2.87 mg/L; r ² values of 0.986, 0.933, 0.942; 0.962, 0.957, and 0.922, respectively.     

Green synthesis of titanium dioxide nanoparticles using Psidium guajava extract and its antibacterial and antioxidant properties

Objective:To determine the efficacies of antibacterial and antioxidant activities of aqueous leaf extract of Psidium guajava mediated biosynthesis of titanium dioxide nanoparticles(TiO_2,NPs).Methods:Synthesized TiO_2 NPs were tested by disc diffusion method against against human pathogenic bacteria.The total antioxidant activity and phenolic content(Folin—Ciocalteau method) of synthesized TiO_2 NTs and aqueous plant extract were determined.The scavenging radicals were estimated hv DPPH method.The synthesized TiO_2 NPs were characterized by XRD,FTIR.FESEM and EDX,Results:FTIR spectra of synthesized TiO_2 NPs exhibited prominent peaks at 3410 cm~(-1)(alkynes),1 578 cm~(-1).1 451 cm~(-1)(alkanes),and 1 123 cm~(-1)(C-O absorption).The morphological characterization of synthesized TiO_2 NPs was analysed by FESEM which showed spherical shape and clusters with an average size of 32.58 nm.The maximum zone of inhibition was observed in the synthesized TiO_2 NPs(20 μg/mL) against Staphylococcus aureus(25 mm) and Escherichia coli(23 mm).The synthesized TiO_2 NPs showed more antibacterial activity than the standard antibiotic disk,tetracycline which drastically reduces the chances for the development of antibiotics resistance of bacterial species.The plant aqueous extract and synthesized TiO_2NPs were found to possess maximum antioxidant activity when compared with ascorbic acid.The content of phenolic compounds(mg/g) in Leaf aqueous extract and synthesized TiO_2 NPs were found to be 85.4 and 18.3 mgTA/g,respectively.Conclusions:Green synthesized TiO_2 NPs provides a promising approach can satisfy the requirement of large-scale industrial production hearing the advantage of low—cost,eco—friendly and reproducible.     

Open Versus Closed Rhinoplasty with Primary Cheiloplasty: A Comparative Study

The repair of unilateral cleft lip nose deformity remains a challenging endeavor for reconstructive surgeons for many reasons, one of which is the timing of rhinoplasty, whether to be synchronous or staged with cleft lip repair and the technique for rhinoplasty. Many authors now favor primary rhinoplasty with the cleft lip repair. Various surgical techniques have been used, most commonly the closed and open rhinoplasty techniques. In this randomized controlled prospective study, we compare the closed rhinoplasty technique with open rhinoplasty during primary unilateral cleft lip repair. Thirty-six patients with unilateral complete cleft lip and nose deformity were selected. Out of this 19 patients were assigned randomly and operated with open rhinoplasty and 17 patients with closed rhinoplasty. The cleft lip repair was done using modified, Millard’s rotation-advancement technique in both the groups. Follow-up assessment was done after 6 months. Quantitative and qualitative analysis were done. Statistical analysis of the data was done using SPSS 11.0. Post-operatively, the alar base width difference between the open and closed rhinoplasty techniques was statistically significant. There was no statistically significant difference in other parameters compared.     

Environmental enrichment upregulates micro‐RNA‐183 and alters acetylcholinesterase splice variants to reduce anxiety‐like behavior in the little Indian field mouse (Mus booduga)

Environmental enrichment (EE) has an influential role in reducing behavioral reactivity to stress. We previously observed that EE reduces the anxiety‐like behavior in the field mouse Mus booduga accompanied by a reduction in the expression of molecules involved in the stress pathway. In this study, we demonstrate the effect of different housing condition on regulation of micro‐RNA‐183‐SC35‐mediated splicing of acetylcholinesterase (AChE). Adult male M. booduga were captured from an agricultural field and housed under nonenriched standard conditions (SC) for 7 days and considered as directly from the wild (DW). On day 8, individuals were randomly assigned to three groups; DW, SC, and EE. The DW group's anxiety‐like behavior was assessed in the elevated plus maze (EPM) and open field test (OFT). The SC and EE groups were transferred to their respective conditions and housed for another 30 days. The mice housed in EE showed less anxiety‐like behavior on EPM and in OFT compared with DW and SC mice. Interestingly, miR‐183 expression was increased following exposure to EPM in EE mice but not in SC mice. Subsequently, the upregulated miR‐183 expression suppresses the SC35 expression and shifting of splicing from AChE‐S (synaptic) to AChE‐R (read‐through) form, whereas standard housing condition downregulate miR‐183 and induces the splicing of AChE. The upregulated AChE‐R form possibly terminates ACh transmission, which is reflected in the level of anxiety‐like behavior. Overall, the present study suggests that EE effectively regulates the miR‐183 pathway to reduce anxiety‐like behavior. © 2012 Wiley Periodicals, Inc.