Fosfomycin: A Substitute in Therapeutic Options for Extended Spectrum Beta-lactamase Producing Uropathogens

Background: The emergence of antibiotic resistance among pathogens causing urinary tract infections (UTI) has made treatment options limited. The use of fosfomycin along with other drug combination can significantly address this problem. Our study aimed to identify the rate of resistance among uropathogens and their susceptibility patterns to fosfomycin along with other antibacterial agents. Methods: The retrospective study was conducted at Jinnah Sindh Medical University in collaboration with Dr. Tahir Laboratory, Karachi. A total of 146 urine samples were included which were processed for antibacterial susceptibility testing by Kirby-Bauer disk diffusion method and rate of resistance for antibacterial agents especially fosfomycin were recorded. The statistical analysis was performed by using Chi squared tests and p>0.05 was considered statistically significant. Results: The study reported lowest rate of resistance for fosfomycin among Escherichia coli 3(5.3%), Klebsiella pneumoniae 7(14%) and Pseudomonas aeruginosa 9(22.5%) in comparison with ampicillin, which showed resistance in 43(76.8%), 41(82%) and 39(97.5%) cases of E. coli, K. pneumoniae and P. aeruginosa respectively. The subgroup carbapenem resistant Enterobacteriaceae (CRE) and extended spectrum β-lactamases (ESBLs) producers were seen noticeably high in P. aeruginosa. Overall, the female to male ratio was 1.4:1 (87/59), showing female preponderance (p=0.02). A majority of patients belonged to adult age group (61.6%) followed by senior adults (23.2%, p=0.05). Conclusion: High levels of resistance to commonly used antibiotics were observed. The increasing rate of resistance among Enterobacteriaceae to cephalosporin and ampicillin is an alarming situation. In this context, fosfomycin is an interesting alternative option in treatment of complicated and uncomplicated urinary tract infections. Keywords: Antibiotic Resistance; Enterobacteriaceae; Extended Spectrum Beta Lactamase; Fosfomycin; Urinary Tract Infection

Low Temperature Synthesis of Superparamagnetic Iron Oxide (Fe3O4) Nanoparticles and Their ROS Mediated Inhibition of Biofilm Formed by Food-Associated Bacteria

In the present study, a facile environmentally friendly approach was described to prepare monodisperse iron oxide (Fe3O4) nanoparticles (IONPs) by low temperature solution route. The synthesized nanoparticles were characterized using x-ray diffraction spectroscopy (XRD), Raman spectroscopy, field emission scanning electron microscopy (FESEM) measurements, Fourier-Transform Infrared Spectroscopy (FTIR), and Thermogravimetric analysis (TGA) analyses. XRD patterns revealed high crystalline quality of the nanoparticles. SEM micrographs showed the monodispersed IONPs with size ranging from 6 to 9 nm. Synthesized nanoparticles demonstrated MICs of 32, 64, and 128 μg/ml against Gram negative bacteria i.e., Serratia marcescens, Escherichia coli, and Pseudomonas aeruginosa, respectively, and 32 μg/ml against Gram positive bacteria Listeria monocytogenes. IOPNs at its respective sub-MICs demonstrated significant reduction of alginate and exopolysaccharide production and subsequently demonstrated broad-spectrum inhibition of biofilm ranging from 16 to 88% in the test bacteria. Biofilm reduction was also examined using SEM and Confocal Laser Scanning Microscopy (CLSM). Interaction of IONPs with bacterial cells generated ROS contributing to reduced biofilm formation. The present study for the first time report that these IONPs were effective in obliterating pre-formed biofilms. Thus, it is envisaged that these nanoparticles with broad-spectrum biofilm inhibitory property could be exploited in the food industry as well as in medical settings to curtail biofilm based infections and losses

Global age-sex-specific mortality, life expectancy, and population estimates in 204 countries and territories and 811 subnational locations, 1950–2021, and the impact of the COVID-19 pandemic: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

Background: Estimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020–21 COVID-19 pandemic period. Methods: 22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 pandemic. 2026 data sources were used for population estimation. Additional sources were used to estimate migration; the effects of the HIV epidemic; and demographic discontinuities due to conflicts, famines, natural disasters, and pandemics, which are used as inputs for estimating mortality and population. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate under-5 mortality rates, which synthesised 30 763 location-years of vital registration and sample registration data, 1365 surveys and censuses, and 80 other sources. ST-GPR was also used to estimate adult mortality (between ages 15 and 59 years) based on information from 31 642 location-years of vital registration and sample registration data, 355 surveys and censuses, and 24 other sources. Estimates of child and adult mortality rates were then used to generate life tables with a relational model life table system. For countries with large HIV epidemics, life tables were adjusted using independent estimates of HIV-specific mortality generated via an epidemiological analysis of HIV prevalence surveys, antenatal clinic serosurveillance, and other data sources. Excess mortality due to the COVID-19 pandemic in 2020 and 2021 was determined by subtracting observed all-cause mortality (adjusted for late registration and mortality anomalies) from the mortality expected in the absence of the pandemic. Expected mortality was calculated based on historical trends using an ensemble of models. In location-years where all-cause mortality data were unavailable, we estimated excess mortality rates using a regression model with covariates pertaining to the pandemic. Population size was computed using a Bayesian hierarchical cohort component model. Life expectancy was calculated using age-specific mortality rates and standard demographic methods. Uncertainty intervals (UIs) were calculated for every metric using the 25th and 975th ordered values from a 1000-draw posterior distribution. Findings: Global all-cause mortality followed two distinct patterns over the study period: age-standardised mortality rates declined between 1950 and 2019 (a 62·8% [95% UI 60·5–65·1] decline), and increased during the COVID-19 pandemic period (2020–21; 5·1% [0·9–9·6] increase). In contrast with the overall reverse in mortality trends during the pandemic period, child mortality continued to decline, with 4·66 million (3·98–5·50) global deaths in children younger than 5 years in 2021 compared with 5·21 million (4·50–6·01) in 2019. An estimated 131 million (126–137) people died globally from all causes in 2020 and 2021 combined, of which 15·9 million (14·7–17·2) were due to the COVID-19 pandemic (measured by excess mortality, which includes deaths directly due to SARS-CoV-2 infection and those indirectly due to other social, economic, or behavioural changes associated with the pandemic). Excess mortality rates exceeded 150 deaths per 100 000 population during at least one year of the pandemic in 80 countries and territories, whereas 20 nations had a negative excess mortality rate in 2020 or 2021, indicating that all-cause mortality in these countries was lower during the pandemic than expected based on historical trends. Between 1950 and 2021, global life expectancy at birth increased by 22·7 years (20·8–24·8), from 49·0 years (46·7–51·3) to 71·7 years (70·9–72·5). Global life expectancy at birth declined by 1·6 years (1·0–2·2) between 2019 and 2021, reversing historical trends. An increase in life expectancy was only observed in 32 (15·7%) of 204 countries and territories between 2019 and 2021. The global population reached 7·89 billion (7·67–8·13) people in 2021, by which time 56 of 204 countries and territories had peaked and subsequently populations have declined. The largest proportion of population growth between 2020 and 2021 was in sub-Saharan Africa (39·5% [28·4–52·7]) and south Asia (26·3% [9·0–44·7]). From 2000 to 2021, the ratio of the population aged 65 years and older to the population aged younger than 15 years increased in 188 (92·2%) of 204 nations. Interpretation: Global adult mortality rates markedly increased during the COVID-19 pandemic in 2020 and 2021, reversing past decreasing trends, while child mortality rates continued to decline, albeit more slowly than in earlier years. Although COVID-19 had a substantial impact on many demographic indicators during the first 2 years of the pandemic, overall global health progress over the 72 years evaluated has been profound, with considerable improvements in mortality and life expectancy. Additionally, we observed a deceleration of global population growth since 2017, despite steady or increasing growth in lower-income countries, combined with a continued global shift of population age structures towards older ages. These demographic changes will likely present future challenges to health systems, economies, and societies. The comprehensive demographic estimates reported here will enable researchers, policy makers, health practitioners, and other key stakeholders to better understand and address the profound changes that have occurred in the global health landscape following the first 2 years of the COVID-19 pandemic, and longer-term trends beyond the pandemic

Asymmetric Synthesis of Nodulones C & D by Chemoenzymatic Approach gives Insight into their Biosynthesis

The first asymmetric total synthesis of fungal secondary metabolites, (R)-nodulone C (4) and trans-nodulone D (5) has been reported through the chemoenzymatic approach. The strategy utilizes NADPH-dependent naphthol reductases of Magnaporthe grisea for the reduction of putative biosynthetic substrates, synthesized non-enzymatically in multiple steps. A dihydronaphthalenone 32 and cis-nodulone D (30) has also been synthesized chemoenzymatically. The work implies for similar steps during the biosynthesis of nodulones and their analogs with the involvement of tetrahydroxynaphthalene reductase related enzyme(s)

Tautomers of Anthrahydroquinones: Enzymatic Reduction and Implications for Chrysophanol, Monodictyphenone, and Related Xanthone Biosyntheses

Reduction of emodin by sodium dithionite resulted in the formation of two tautomeric forms of emodin hydroquinone. Subsequent conversion by the short-chain dehydrogenase/reductase (SDR) MdpC into the corresponding 3-hydroxy-3,4-dihydroanthracen-1­(2<i>H</i>)-one implies that deoxygenation is the first step in monodictyphenone biosynthesis. Implications for chrysophanol formation as well as reaction sequences in the related xanthone, ergochrome, and bianthraquinone biosyntheses are discussed

Tautomers of Anthrahydroquinones: Enzymatic Reduction and Implications for Chrysophanol, Monodictyphenone, and Related Xanthone Biosyntheses

Reduction of emodin by sodium dithionite resulted in the formation of two tautomeric forms of emodin hydroquinone. Subsequent conversion by the short-chain dehydrogenase/reductase (SDR) MdpC into the corresponding 3-hydroxy-3,4-dihydroanthracen-1­(2<i>H</i>)-one implies that deoxygenation is the first step in monodictyphenone biosynthesis. Implications for chrysophanol formation as well as reaction sequences in the related xanthone, ergochrome, and bianthraquinone biosyntheses are discussed

Highly Efficient One-Pot Multienzyme Cascades for the Stereoselective Synthesis of Natural Naphthalenones

Herein, a biocatalytic cascade containing an ene-reductase (NostocER) and naphthol reductase (tetrahydroxynaphthalene or trihydroxynaphthalene reductase) of Magnaporthe grisea and NADPH is developed. The optimized multienzyme cascade is applied for the one-pot reduction of plumbagin to obtain biologically active cis-(3R,4R)-isoshinanolone, with drcis:trans 98:2 and >99% ee in 96% yield. Furthermore, naturally occurring (+)-isosclerone, (+)-shinanolone, (−)-shinanolone, and (S)-4-hydroxy-3,4-dihydronaphthalen-1­(2H)-one were also synthesized with excellent stereoselectivity and high yields (71–89%) using the enzymatic cascades. The investigation of NostocER–T4HNR-cascade reduction of menadione, plumbagin, and 5-methoxymenadione revealed specificity of tetrahydroxynaphthalene reductase toward these substrates. In addition, the kinetic studies showed a high catalytic efficiency of NostocER and T4HNR toward plumbagin and dihydroplumbagin, respectively, compared to other enzymes

Biomimetic Asymmetric Synthesis of (<i>R</i>)-GTRI-02 and (3<i>S</i>,4<i>R</i>)-3,4-Dihydroxy-3,4-dihydronaphthalen-1(2<i>H</i>)-ones

The NADPH-dependent tetrahydroxynaphthalene reductase (T₄HNR) from <i>Magnaporthe grisea</i> was used for the biomimetic synthesis of (<i>R</i>)-GTRI-02 by stereoselective reduction of 1-(3,6,8-trihydroxy-1-methylnaphthalen-2-yl)ethanone. This also led to the isolation of a (3<i>S</i>,4<i>R</i>)-<i>cis</i>-ketodiol formed by T₄HNR-catalyzed reduction of the corresponding hydroxynaphthoquinone. Flaviolin and lawsone also reduced to corresponding <i>cis</i>-ketodiols in good yields

Biomimetic Asymmetric Synthesis of (<i>R</i>)-GTRI-02 and (3<i>S</i>,4<i>R</i>)-3,4-Dihydroxy-3,4-dihydronaphthalen-1(2<i>H</i>)-ones

The NADPH-dependent tetrahydroxynaphthalene reductase (T₄HNR) from <i>Magnaporthe grisea</i> was used for the biomimetic synthesis of (<i>R</i>)-GTRI-02 by stereoselective reduction of 1-(3,6,8-trihydroxy-1-methylnaphthalen-2-yl)ethanone. This also led to the isolation of a (3<i>S</i>,4<i>R</i>)-<i>cis</i>-ketodiol formed by T₄HNR-catalyzed reduction of the corresponding hydroxynaphthoquinone. Flaviolin and lawsone also reduced to corresponding <i>cis</i>-ketodiols in good yields