Design, synthesis and evaluation of indole-2-carboxamides with pan anti-mycobacterial activity.

Current treatment regimens for non-tuberculous mycobacteria (NTM) and tuberculosis (TB) generally require long duration of therapy with multiple drugs, some of which are broad spectrum antibiotics. Despite some advances in antimicrobial compounds, there remains a need in therapy for antibiotics with specific mycobacterial targets. It has been shown that MmpL3 is an essential transporter required for the translocation of mycolic acids to the mycobacterial cell envelope. Here, we synthesized a series of indole-2-carboxamides that inhibit MmpL3 and have potent pan-activity against mycobacterial species. The compounds were tested against several fast and slow-growing Mycobacterium species, including M. abscessus, M. massiliense, M. bolletii, M. chelonae, M. tuberculosis, M. avium, M. xenopi and M. smegmatis. The target of these indole-based compounds makes them selective for mycobacteria, while showing no clinically relevant bactericidal activity against S. aureus or P. aeruginosa. These compounds were tested against THP-1, a human-cell line, and showed minimal in vitro cytotoxicity and good selectivity indices. The data shown and discussed suggest that lead indole-2-carboxamides are strong contenders for further preclinical testing as NTM therapeutics.

Optimization of the acetic acid method for microfossil extraction from lithified carbonate rocks: Examples from the Jurassic and Miocene limestones of Saudi Arabia.

An optimization experiment with different acid concentrations was carried out to assess the use of acid to minimum sustainable limits for the extraction of microfossils from indurated limestones. Two different limestone formations of Jurassic and Miocene ages were tested. Different concentrations of acid ranging from 50 to 100% and processing times varying from 2 to 10 h were tested for optimal recoveries. The acid residue recoveries show a similar trend for both formations. The weight percentage of residue with particle size >1 mm decreased as the acid concentration increased, especially in the 50-80% acid concentration range. On the other hand, the weight percentage of the smallest size particles > 0.063 mm increased as acid concentration increased. This means that the higher concentrations of acid dissolve more of the unnecessary large particles while the foraminifera, which comprise the sand fraction size, are left in the residue. Although higher acid concentrations with longer reaction times yielded better recoveries than with less reaction time, we recommended a 60% concentration of acetic acid and a reaction time of 10 h for optimal recovery of micropaleontological samples in Saudi Arabian carbonate rocks. By lowering the recommended concentration, the consumption of acid is reduced without compromising the recovery of microfossils.•Acetic acid leaching method is applied on two different age limestone samples to extract foraminifera.•Different concentrations of acetic acid are tried and tested, and consensus is made on an optimum concentration of 60% for a submersion time of 10 h.•The sample recoveries are optimal while using this concentration for a time of 10 h.

Recommendation for a non-animal alternative to rat caries testing.

PURPOSE: As a requirement of the Food & Drug Administration's final monograph on "Anticaries drug products for over-the-counter human use", the toothpaste industry has been conducting animal caries tests on every fluoride-containing toothpaste introduced into the U.S. market since 1996. The practice of testing in animals, although required by law, is in stark conflict with the corporate policy of many U.S. and global toothpaste manufacturers, in which, if possible, alternatives to animal testing are utilized. A provision does exist within the regulation which allows the use of an alternative method to demonstrate efficacy. However, to take advantage of this provision, a petition must be submitted to the FDA and in this petition data demonstrating the alternative provides results of "equivalent accuracy" must be included. After many years of research, model development and model comparisons, we have identified one particular laboratory model that demonstrated excellent correlation with the currently accepted animal caries models. This model, known as the Featherstone pH cycling model, is discussed in this paper. METHODS: The Featherstone pH cycling model has been shown to produce results of equivalent accuracy to the animal caries model by: (1) demonstrating a clinically relevant fluoride dose response similar to that shown in the animal caries model (including 1100 ppm F, 250 ppm F and placebo); (2) demonstrating similar results to the animal caries model for clinically proven dentifrice formulations relative to positive and negative controls; (3) demonstrating discriminating ability in strong agreement with the animal caries model for differentiating between a dentifrice formulation with attenuated fluoride activity and a USP standard; and (4) providing a clinically relevant representation of the caries process, as demonstrated by orthodontic banding studies. In addition, the model sufficiently addresses both salivary and abrasive/anticalculus agent interference concerns. RESULTS: For more than 50 years, fluoride has been the first defense in the fight against dental caries. The clinical effectiveness of fluoride is well accepted and documented extensively in the literature. The mechanism through which fluoride provides its benefit is very straightforward and well understood. The proposed laboratory model effectively simulates the effect of the caries process and has been shown to demonstrate equivalent accuracy to animal caries. This indicates that there are strong scientific grounds for the use of this model as an alternative to the animal caries test. Based on the strength of the data and the correlations noted between the two models, we recommend that the scientific community and the toothpaste industry broadly accept the Featherstone laboratory pH cycling model as an appropriate alternative to animal testing, particularly for ionic fluoride based dentifrices.

The Featherstone laboratory pH cycling model: a prospective, multi-site validation exercise.

PURPOSE: To demonstrate the robustness of the Featherstone pH cycling model when tested in three independent laboratories and to evaluate the use of "non-inferiority" testing at those laboratories. METHODS: The fundamental principles for the Featherstone laboratory pH cycling model to be an appropriate alternative to animal testing is that it must demonstrate equivalent accuracy to the "Gold Standard" (rat caries model) by: (1) providing a meaningful representation of the caries process; (2) demonstrating a proportionate response to fluoride dose (or concentration); (3) being able to show that clinically proven formulations perform similarly relative to the controls; and (4) differentiating products that have attenuated fluoride activity. RESULTS: This cross-validation study confirmed the ability of the three independent laboratories to discriminate between various concentrations of fluoride-containing dentifrice formulations, demonstrated that clinically proven formulas perform as expected and identified an attenuated fluoride formulation (NaF/CaCO3 dentifrice - 1100 ppm NaF) as inferior compared to the 1100 ppm F (NaF/silica) positive control.

Sediment oxygen demand and benthic foraminiferal faunas in the Arabian Gulf: A test of the method on a siliciclastic substrate.

In this study, we investigated the relationship between environmental parameters (water and sediment) and benthic foraminiferal assemblages found in nearshore siliciclastic sediment in the Arabian Gulf. Nearshore marine water and sediment samples were collected from a beach on the Gulf of Bahrain located south of Al Khobar, Saudi Arabia. The water samples were analyzed for biochemical oxygen demand (BOD5) and other chemical analyses. The sediment samples were tested for sediment oxygen demand (SOD) and heavy metal analysis. Results showed the BOD5 levels were below the detection limit (<1 ppm), while the mean SOD value was 0.97 ± 0.08 g/m2·day. The water and sediments were unpolluted and free of eutrophic enrichment, while the sediment was anoxic. The two most common genera in the benthic foraminiferal assemblage, Ammonia and Elphidium, are typical of shallow water sandy substrates. This is the first reported comparison between SOD and benthic foraminiferal assemblages.

Dataset showing the abundance and distribution of benthic foraminifera in relation to marine sediment parameters from western Arabian Gulf.

This dataset supports the paper entitled "A baseline investigation of benthic foraminifera in relation to marine sediments parameters in western parts of the Arabian Gulf". Duplicate sediment samples (sets A and B) were collected from 30 stations in an area covering approximately 25000 km2 in the offshore northern Arabian Gulf, using a van Veen grab (0.1 m2 area) and the top 1 cm was analysed for living benthic foraminifera. A set of samples was devoted to foraminiferal analysis while the other, set B, for sediment analyses. In situ hydrographical parameters such as temperature, salinity, pH, turbidity and DO were measured at surface waters. The top 1 cm was subsampled for foraminiferal analyses from the grab and preserved using 70% ethanol with Rose-Bengal stain. Potentially Toxic Elements (PTE) levels in sediment and grain size distributions were analysed. The dataset is expected to provide a baseline for PTE levels in sediment, benthic foraminiferal communities, and identify endemic species adapted to extremes of temperature and saline conditions typical of the Gulf. It can also be used by environmental managers, micropaleotologists, students in environmental/geology/marine science as reference background conditions based on sediment toxicity and benthic community information in revising environmental guidelines in the region. Data from this study suggest that PTEs are within the range of background values, and the sediments support highly diversified and stable benthic foraminiferal communities adapted to the unique environmental conditions in the Gulf. To date, this dataset documents the highest number of living benthic foraminifera species reported from the Gulf, and the most diverse living community compared to all previous studies. It also provides evidence for the full recovery of areas impacted during the 1991 Gulf oil spill which is evident by the diverse and flourishing assemblages of living benthic foraminifera documented.

Pleistocene epilithic foraminifera from the Arctic Ocean.

Attached epilithic foraminifera constitute an important but overlooked component of the benthic foraminiferal assemblage in the Pleistocene sediment of the central Arctic Ocean. We report 12 types of epilithic foraminifera that have colonised lithic and biogenic grains found in glacial sediments, including representatives of the genera Rhizammina, Hemisphaerammina, Ammopemphix, Diffusilina, Subreophax, Placopsilina, Placopsilinella, Hormosinelloides and Tholosina, accompanied by mat-like and ribbon-like forms of uncertain taxonomic affinity. The attached agglutinated forms appear to be colonisers, adapted to extremely oligotrophic conditions.

A baseline investigation of benthic foraminifera in relation to marine sediments parameters in western parts of the Arabian Gulf.

This baseline paper discusses the distribution and abundance of living benthic foraminifera in relation to Potentially Toxic Elements (PTEs) such as As, Al, Fe Cd, Co, Cr, Cu, V, Ni, Hg, Pb, and Zn in marine sediments collected from 30 stations in the offshore Arabian Gulf to define baseline environmental conditions for the implementation of future biomonitoring programs. A total of 271 living benthic foraminiferal species were identified belonging to 66 genera, 37 families and 6 orders. Data from this work suggest that PTEs are within the range of background values, and the sediments support highly diversified and stable benthic foraminiferal communities adapted to the unique environmental conditions in the Gulf. Thus, the effect of anthropogenic activities is deemed negligible. This study is expected to provide a baseline dataset for PTE levels in sediment, benthic foraminiferal communities, and identify endemic species adapted to extremes of temperature and saline conditions typical of the Gulf.

Activity of amine oxide against biofilms of Streptococcus mutans: a potential biocide for oral care formulations.

AIMS: To assess the potential bactericidal activity of amine oxide (C10-C16-alkyldimethyl N-oxides) against Streptococcus mutans grown as planktonic suspension and as biofilm on hydroxyapatite discs, and its ability to control acidification of the media. METHODS: Amine oxide bacteriostasis was investigated using the Bioscreen C Microbiological Growth Analyser, while a standard suspension test was used to determine its bactericidal efficacy. In addition, the lethal activity of amine oxide was studied against sedimentation biofilms of S. mutans on hydroxyapatite (HA) discs and resuspended biofilms. Several parameters were considered such as the surfactant concentration, pH, the starting inoculum and the maturity of the biofilm. RESULTS: Amine oxide was bacteriostatic against planktonic S. mutans at a low concentration (0.006% v/v) and highly bactericidal against S. mutans in suspension or in a mature biofilm on hydroxyapatite, although the concentration required to achieve the latter effect was four times higher. The activity of amine oxide against biofilms depended upon its concentration and the age of the biofilm. In addition, amine oxide pre-treatment of the HA discs did not affect the growth of the biofilm. Finally, amine oxide did not prevent the acidification of the medium, although lower pHs had a potentiating effect on amine oxide activity. CONCLUSION: Amine oxide showed high potential for controlling early biofilms caused by periodontal bacteria. Further investigations should be carried out, particularly on the potential toxicity of amine oxide and its efficacy in complex formulations for oral care products.