Discovery of novel phthalimide analogs

In continuation of our endeavor towards the design and development of potent and effective antimicrobial agents, three series of phthalimide derivatives (4a–i, 5a–f, and 6a-c) were synthesized, fully characterized and evaluated for their potential antibacterial, antifungal and antimycobacterial activities. These efforts led to the discovery of nine compounds 4c, 4f, 4g, 4h, 4i, 5c, 5d, 5e, and 6c (MIC range from 0.49 to 31.5 μg/mL) with potent antibacterial, antifungal, and antimycobacterial activities. Ampicillin, ciprofloxacin, amphotericin B were used as references for antibacterial and antifungal screening respectively, while isoniazid was used as a reference for antimycobacterial testing. Furthermore, molecular modeling studies were done to explore the binding mode of the most active derivatives to M. tuberculosis enoyl reductase (InhA) and DNA gyrase B. Our study showed the importance of both hydrogen bonding and hydrophobic interactions as a key interaction with the target enzymes

Linkages between GRACE water storage, hydrologic extremes, and climate teleconnections in major African aquifers

Water resources management is a critical issue in Africa where many regions are subjected to sequential droughts and floods. The objective of our work was to assess spatiotemporal variability in water storage and related controls (climate, human intervention) in major African aquifers and consider approaches toward more sustainable development. Different approaches were used to track water storage, including GRACE/GRACE Follow On satellites for Total Water Storage (TWS); satellite altimetry for reservoir storage, MODIS satellites for vegetation indices, and limited ground-based monitoring. Results show that declining trends in TWS (60–73 km3 over the 18 yr GRACE record) were restricted to aquifers in northern Africa, controlled primarily by irrigation water use in the Nubian and NW Saharan aquifers. Rising TWS trends were found in aquifers in western Africa (23–49 km3), attributed to increased recharge from land use change and cropland expansion. Interannual variability dominated TWS variability in eastern and southern Africa, controlled primarily by climate extremes. Climate teleconnections, particularly El Nino Southern Oscillation and Indian Ocean Dipole, strongly controlled droughts and floods in eastern and southern Africa. Huge aquifer storage in northern Africa suggests that the recent decadal storage declines should not impact the regional aquifers but may affect local conditions. Increasing groundwater levels in western Africa will need to be managed because of locally rising groundwater flooding. More climate resilient water management can be accomplished in eastern and southern Africa by storing water from wet to dry climate cycles. Accessing the natural water storage provided by aquifers in Africa is the obvious way to manage the variability between droughts and floods

Discovery of two brominated oxindole alkaloids as staphylococcal DNA gyrase and pyruvate kinase inhibitors via inverse virtual screening

In the present study, a small marine-derived natural products library was assessed for antibacterial potential. Among 36 isolated compounds, a number of bis-indole derivatives exhibited growth-inhibitory activity towards Gram-positive strains (Bacillus subtilis and multidrug-resistant Staphylococcus aureus). 5- and 6-trisindoline (5-Tris and 6-Tris) were the most active derivatives (minimum inhibitory concentration, MIC, 4–8 µM) that were subsequently selected for anti-biofilm activity evaluation. Only 5-Tris was able to inhibit the staphylococcal biofilm formation starting at a 5 µM concentration. In order to investigate their possible molecular targets, both natural products were subjected to in silico inverse virtual screening. Among 20 target proteins, DNA gyrase and pyruvate kinase were the most likely to be involved in the observed antibacterial and anti-biofilm activities of both selected natural products. The in vitro validation and in silico binding mode studies revealed that 5-Tris could act as a dual enzyme inhibitor (IC50 11.4 ± 0.03 and 6.6 ± 0.05 µM, respectively), while 6-Tris was a low micromolar gyrase-B inhibitor (IC50 2.1 ± 0.08 µM), indicating that the bromine position plays a crucial role in the determination of the antibacterial lead compound inhibitory activity

Flavonoid-coated gold nanoparticles as efficient antibiotics against gram-negative bacteria—evidence from in silico-supported in vitro studies

Flavonoids are a class of bioactive plant-derived natural products that exhibit a broad range of biological activities, including antibacterial ones. Their inhibitory activity toward Gram-positive bacterial was found to be superior to that against Gram-negative ones. In the present study, a number of flavonoid-coated gold nanoparticles (GNPs) were designed to enhance the antibacterial effects of chrysin, kaempferol, and quercetin against a number of Gram-negative bacteria. The prepared GNPs were able to conjugate to these three flavonoids with conjugation efficiency ranging from 41% to 80%. Additionally, they were able to exert an enhanced antibacterial activity in comparison with the free flavonoids and the unconjugated GNPs. Quercetin-coated GNPs were the most active nano-conjugates and were able to penetrate the cell wall of E. coli. A number of in silico experiments were carried out to explain the conjugation efficiency and the antibacterial mechanisms of these flavonoids as follows: (i) these flavonoids can efficiently bind to the glutathione linker on the surface of GNPs via H-bonding; (ii) these flavonoids, particularly quercetin, were able to increase the bacterial membrane rigidity, and hence decrease its functionality; (iii) these flavonoids can inhibit E. coli’s DNA gyrase (Gyr-B) with IC(50) values ranging from 0.9 to 3.9 µM. In conclusion, these bioactive flavonoid-based GNPs are considered to be very promising antibiotic candidates for further development and evaluation

New Pim-1 Kinase Inhibitor From the Co-culture of Two Sponge-Associated Actinomycetes

Saccharomonospora sp. UR22 and Dietzia sp. UR66, two actinomycetes derived from the Red Sea sponge Callyspongia siphonella, were co-cultured and the induced metabolites were monitored by HPLC-DAD and TLC. Saccharomonosporine A (1), a novel brominated oxo-indole alkaloid, convolutamydine F (2) along with other three known induced metabolites (3-5) were isolated from the EtOAc extract of Saccharomonospora sp. UR22 and Dietzia sp. UR66 co-culture. Additionally, axenic culture of Saccharomonospora sp. UR22 led to isolation of six known microbial metabolites (6-11). A kinase inhibition assay results showed that compounds 1 and 3 were potent Pim-1 kinase inhibitors with an IC50 value of 0.3 ± 0.02 and 0.95 ± 0.01 μM, respectively. Docking studies revealed the binding mode of compounds 1 and 3 in the ATP pocket of Pim-1 kinase. Testing of compounds 1 and 3 displayed significant antiproliferative activity against the human colon adenocarcinoma HT-29, (IC50 3.6 and 3.7 μM, respectively) and the human promyelocytic leukemia HL-60, (IC50 2.8 and 4.2 μM, respectively). These results suggested that compounds 1 and 3 act as potential Pim-1 kinase inhibitors that mediate the tumor cell growth inhibitory effect. This study highlighted the co-cultivation approach as an effective strategy to increase the chemical diversity of the secondary metabolites hidden in the genomes of the marine actinomycetes

Induction of antibacterial metabolites by co-cultivation of two Red-Sea-sponge-associated actinomycetes <i>Micromonospora</i> sp. UR56 and <i>Actinokinespora</i> sp. EG49

Liquid chromatography coupled with high resolution mass spectrometry (LC-HRESMS)-assisted metabolomic profiling of two sponge-associated actinomycetes, Micromonospora sp. UR56 and Actinokineospora sp. EG49, revealed that the co-culture of these two actinomycetes induced the accumulation of metabolites that were not traced in their axenic cultures. Dereplication suggested that phenazine-derived compounds were the main induced metabolites. Hence, following large-scale co-fermentation, the major induced metabolites were isolated and structurally characterized as the already known dimethyl phenazine-1,6-dicarboxylate (1), phenazine-1,6-dicarboxylic acid mono methyl ester (phencomycin; 2), phenazine-1-carboxylic acid (tubermycin; 3), N-(2-hydroxyphenyl)-acetamide (9), and p-anisamide (10). Subsequently, the antibacterial, antibiofilm, and cytotoxic properties of these metabolites (1&ndash;3, 9, and 10) were determined in vitro. All the tested compounds except 9 showed high to moderate antibacterial and antibiofilm activities, whereas their cytotoxic effects were modest. Testing against Staphylococcus DNA gyrase-B and pyruvate kinase as possible molecular targets together with binding mode studies showed that compounds 1&ndash;3 could exert their bacterial inhibitory activities through the inhibition of both enzymes. Moreover, their structural differences, particularly the substitution at C-1 and C-6, played a crucial role in the determination of their inhibitory spectra and potency. In conclusion, the present study highlighted that microbial co-cultivation is an efficient tool for the discovery of new antimicrobial candidates and indicated phenazines as potential lead compounds for further development as antibiotic scaffold

Assessment of Global Kidney Health Care Status.

Kidney disease is a substantial worldwide clinical and public health problem, but information about available care is limited.To collect information on the current state of readiness, capacity, and competence for the delivery of kidney care across countries and regions of the world.Questionnaire survey administered from May to September 2016 by the International Society of Nephrology (ISN) to 130 ISN-affiliated countries with sampling of key stakeholders (national nephrology society leadership, policy makers, and patient organization representatives) identified by the country and regional nephrology leadership through the ISN.Core areas of country capacity and response for kidney care.Responses were received from 125 of 130 countries (96%), including 289 of 337 individuals (85.8%, with a median of 2 respondents [interquartile range, 1-3]), representing an estimated 93% (6.8 billion) of the world's population of 7.3 billion. There was wide variation in country readiness, capacity, and response in terms of service delivery, financing, workforce, information systems, and leadership and governance. Overall, 119 (95%), 95 (76%), and 94 (75%) countries had facilities for hemodialysis, peritoneal dialysis, and kidney transplantation, respectively. In contrast, 33 (94%), 16 (45%), and 12 (34%) countries in Africa had facilities for hemodialysis, peritoneal dialysis, and kidney transplantation, respectively. For chronic kidney disease (CKD) monitoring in primary care, serum creatinine with estimated glomerular filtration rate and proteinuria measurements were reported as always available in only 21 (18%) and 9 (8%) countries, respectively. Hemodialysis, peritoneal dialysis, and transplantation services were funded publicly and free at the point of care delivery in 50 (42%), 48 (51%), and 46 (49%) countries, respectively. The number of nephrologists was variable and was low (<10 per million population) in Africa, the Middle East, South Asia, and Oceania and South East Asia (OSEA) regions. Health information system (renal registry) availability was limited, particularly for acute kidney injury (8 countries [7%]) and nondialysis CKD (9 countries [8%]). International acute kidney injury and CKD guidelines were reportedly accessible in 52 (45%) and 62 (52%) countries, respectively. There was relatively low capacity for clinical studies in developing nations.This survey demonstrated significant interregional and intraregional variability in the current capacity for kidney care across the world, including important gaps in services and workforce. Assuming the responses accurately reflect the status of kidney care in the respondent countries, the findings may be useful to inform efforts to improve the quality of kidney care worldwide

¹H-NMR metabolic profiling, antioxidant activity, and docking study of common medicinal plant-derived honey

The purpose of this investigation was to determine &sup1;H-NMR profiling and antioxidant activity of the most common types of honey, namely, citrus honey (HC1) (Morcott tangerine L. and Jaffa orange L.), marjoram honey (HM1) (Origanum majorana L.), and clover honey (HT1) (Trifolium alexandrinum L.), compared to their secondary metabolites (HC2, HM2, HT2, respectively). By using a &sup1;H-NMR-based metabolomic technique, PCA, and PLS-DA multivariate analysis, we found that HC2, HM2, HC1, and HM1 were clustered together. However, HT1 and HT2 were quite far from these and each other. This indicated that HC1, HM1, HC2, and HM2 have similar chemical compositions, while HT1 and HT2 were unique in their chemical profiles. Antioxidation potentials were determined colorimetrically for scavenging activities against DPPH, ABTS, ORAC, 5-LOX, and metal chelating activity in all honey extract samples and their secondary metabolites. Our results revealed that HC2 and HM2 possessed more antioxidant activities than HT2 in vitro. HC2 demonstrated the highest antioxidant effect in all assays, followed by HM2 (DPPH assay: IC50 2.91, 10.7 &mu;g/mL; ABTS assay: 431.2, 210.24 at 50 ug/mL Trolox equivalent; ORAC assay: 259.5, 234.8 at 50 ug/mL Trolox equivalent; 5-LOX screening assay/IC50: 2.293, 6.136 ug/mL; and metal chelating activity at 50 ug/mL: 73.34526%, 63.75881% inhibition). We suggest that the presence of some secondary metabolites in HC and HM, such as hesperetin, linalool, and caffeic acid, increased the antioxidant activity in citrus and marjoram compared to clover honey

Dihydrophenazine:a multifunctional new weapon that kills multidrug-resistant Acinetobacter baumannii and restores carbapenem and oxidative stress susceptibilities

AimsThe current work aims to fully characterize a new antimicrobial agent against Acinetobacter baumannii, which continues to represent a growing threat to healthcare settings worldwide. With minimal treatment options due to the extensive spread of resistance to almost all the available antimicrobials, the hunt for new antimicrobial agents is a high priority. Methods and resultsAn Egyptian soil-derived bacterium strain NHM-077B proved to be a promising source for a new antimicrobial agent. Bioguided fractionation of the culture supernatants of NHM-077B followed by chemical structure elucidation identified the active antimicrobial agent as 1-hydroxy phenazine. Chemical synthesis yielded more derivatives, including dihydrophenazine (DHP), which proved to be the most potent against A. baumannii, yet it exhibited a safe cytotoxicity profile against human skin fibroblasts. Proteomics analysis of the cells treated with DHP revealed multiple proteins with altered expression that could be correlated to the observed phenotypes and potential mechanism of the antimicrobial action of DHP. DHP is a multi-pronged agent that affects membrane integrity, increases susceptibility to oxidative stress, interferes with amino acids/protein synthesis, and modulates virulence-related proteins. Interestingly, DHP in sub-inhibitory concentrations resensitizes the highly virulent carbapenem-resistant A. baumannii strain AB5075 to carbapenems providing great hope in regaining some of the benefits of this important class of antibiotics. ConclusionsThis work underscores the potential of DHP as a promising new agent with multifunctional roles as both a classical and non-conventional antimicrobial agent that is urgently needed.<br/

Metabolomic profile, anti-trypanosomal potential and molecular docking studies of <i>Thunbergia grandifolia</i>

Trypanosomiasis is a protozoan disease transmitted via Trypanosoma brucei. This study aimed to examine the metabolic profile and anti-trypanosomal effect of methanol extract of Thunbergia grandifolia leaves. The liquid chromatography-high resolution electrospray ionisation mass spectrometry (LC-HRESIMS) revealed the identification of fifteen compounds of iridoid, flavonoid, lignan, phenolic acid, and alkaloid classes. The extract displayed a promising inhibitory activity against T. brucei TC 221 with MIC value of 1.90 μg/mL within 72 h. A subsequent in silico analysis of the dereplicated compounds (i.e. inverse docking, molecular dynamic simulation, and absolute binding free energy) suggested both rhodesain and farnesyl diphosphate synthase as probable targets for two compounds among those dereplicated ones in the plant extract (i.e. diphyllin and avacennone B). The absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling of diphyllin and avacennone were calculated accordingly, where both compounds showed acceptable drug-like properties. This study highlighted the antiparasitic potential of T. grandifolia leaves