Development of Non-Natural Flavanones as Antimicrobial Agents

With growing concerns over multidrug resistance microorganisms, particularly strains of bacteria and fungi, evolving to become resistant to the antimicrobial agents used against them, the identification of new molecular targets becomes paramount for novel treatment options. Recently, the use of new treatments containing multiple active ingredients has been shown to increase the effectiveness of existing molecules for some infections, often with these added compounds enabling the transport of a toxic molecule into the infecting species. Flavonoids are among the most abundant plant secondary metabolites and have been shown to have natural abilities as microbial deterrents and anti-infection agents in plants. Combining these ideas we first sought to investigate the potency of natural flavonoids in the presence of efflux pump inhibitors to limit Escherichia coli growth. Then we used the natural flavonoid scaffold to synthesize non-natural flavanone molecules and further evaluate their antimicrobial efficacy on Escherichia coli, Bacillus subtilis and the fungal pathogens Cryptococcus neoformans and Aspergillus fumigatus. Of those screened, we identified the synthetic molecule 4-chloro-flavanone as the most potent antimicrobial compound with a MIC value of 70 µg/mL in E. coli when combined with the inhibitor Phe-Arg-ß-naphthylamide, and MICs of 30 µg/mL in S. cerevesiae and 30 µg/mL in C. neoformans when used alone. Through this study we have demonstrated that combinatorial synthesis of non-natural flavonones can identify novel antimicrobial agents with activity against bacteria and fungi but with minimal toxicity to human cells

Dichrostachys cinerea (L.) Wight et Arn (Mimosaceae) hydro-alcoholic extract action on the contractility of tracheal smooth muscle isolated from guinea-pig

<p>Abstract</p> <p>Background</p> <p><it>Dichrostachys cinerea </it>(L.) Wight et Arn. (Mimosaceae) is largely used in ethno-medically across Africa, and mainly employed for the treatment of asthma in Ivory Coast and Gabon. The paper analyses the relaxation induced by the methanolic extract of <it>D. cinerea </it>(Edici) in the guinea-pig trachea preparations (GPTPs). Purpose: This study aimed to bring out the scientific basis to the use of this plant leading to the validation of this phytomedicine.</p> <p>Method</p> <p>The aorta obtained from guinea-pigs was immediately placed in a Mac Ewen solution. Experiments were performed in preparations suspended between two L-shaped stainless steel hooks in a 10 ml organ bath containing Mac Ewen solution. The isometric contractile force of the aorta strips of guinea-pig were recorded by using a strain gauge. The different drugs were directly administered into the organ bath and the magnitude of GPTPs was evaluated.</p> <p>Results</p> <p>Phytochemical analysis of the methanolic extract of Dichrostachys <it>cinerea </it>(Edici) using chemical methods revealed the presence of flavenoids, tannins, sterols, triterpenes and polyphenols. Pharmacological studies performed in GPTPs show that of <it>Dichrostachys cinerea </it>(0.1 mg/ml - 2 mg/ml) evoked a broncho-constriction in GPTPs. Whereas, at concentration up to 2 mg/ml, Edici induced a significant dose-dependent relaxation in the GPTPs. KCl-, ACh- or histamine-evoked contractions of isolated trachea was significantly inhibited by increasing concentrations of Edici (3.5-10 mg/ml). Edici (10 mg/ml) as well as promethazine (0.25 mg/ml) significantly inhibited contractions induced by increasing concentrations of histamine (1×10^-7-1×10^-4mg/ml). In the presence of atropine at a concentration of 10^-6mg/ml, contractile response curve (CRC) evoked by ACh (1×10^-5-1×10^-2mg/ml) was significantly abolished in concentration-dependent manner. Edici did not significantly reduced ACh evoked contraction (10^-5-10^-2mg/ml).</p> <p>Conclusion</p> <p>These observations suggest that Edici could act through two mechanisms: firstly by activation of β-adrenergic or histaminergic receptors; and secondly muscarinic receptors may not be greatly involved, that justifying the use of the extract in traditional Medicine in Africa.</p

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Browser selectivity alters post-fire competition between Erica arborea and E. trimera in the sub-alpine heathlands of Ethiopia

Mammalian herbivores have the potential to alter the competitive relations of woody species, if consumption is unevenly distributed between species. At elevations above 3500 m in the southern Ethiopian highlands, vegetation is dominated by Erica arborea and Erica trimera. Both species can potentially grow into short trees, but are burnt on a rotation of 6 to 10 years, and regenerate by re-sprouting from belowground lignotubers. The regenerating scrub is heavily browsed by cattle. We set up browsing exclosures at three burnt sites to quantify the impact of browsing over a three-year period. When protected from browsing, E. trimera had similar or better height growth than Erica arborea, but in browsed vegetation, Erica arborea instead grew taller. Browsing was more intense on E. trimera in the first years after fire, indicating a difference in palatability between the species. We checked if browse quality differed, by analysing shoot contents of acid detergent fibre, protein, phenolics and tannins. Contrary to expectations the preferred E. trimera contained more acid detergent fibre, less protein and had a higher tannin activity than E. arborea. Although the vegetative growth of E. arborea is favoured relative to E. trimera under high browsing pressure, rapid change in abundance would not be expected, since short-interval fire will repeatedly eradicate any gains in vegetative growth. However, within the typical fire return interval of less than 10 years, E. trimera barely reach a reproductive state, whereas E. arborea flower profusely. Under the current regime of fire and browsing this may in the long run be more important than differences in height growth, leading to a gradual increase in the proportion of E. arborea