Selective Trihydroxylated Azepane Inhibitors of NagZ, a Glycosidase Involved in Pseudomonas Aeruginosa Resistance to β-lactam Antibiotics

The synthesis of a series of D-gluco-like configured 4,5,6-trihydroxyazepanes bearing a triazole, a sulfonamide or a fluorinated acetamide moiety at C-3 is described. These synthetic derivatives have been tested for their ability to selectively inhibit the muropeptide recycling glucosaminidase NagZ and to thereby increase sensitivity of Pseudomonas aeruginosa to β-lactams, a pathway with substantial therapeutic potential. While introduction of triazole and sulfamide groups failed to lead to glucosaminidase inhibitors, the NHCOCF3 analog proved to be a selective inhibitor of NagZ over other glucosaminidases including human OGA and lysosomal hexosaminidases HexA and B. The synthesis of a series of D-gluco-like configured 4,5,6-trihydroxyazepanes bearing a triazole, a sulfonamide or a fluorinated acetamide moiety at C-3 is described. These synthetic derivatives have been tested for their ability to selectively inhibit the muropeptide recycling glucosaminidase NagZ and to thereby increase sensitivity of Pseudomonas aeruginosa to β-lactams, a pathway with substantial therapeutic potential. While introduction of triazole and sulfamide groups failed to lead to glucosaminidase inhibitors, the NHCOCF3 analog proved to be a selective inhibitor of NagZ over other glucosaminidases including human OGA and lysosomal hexosaminidases HexA and B &nbsp

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Anti-retroviral and cytostatic activity of 2',3'-dideoxyribonucleotide 3'-disulfides.

International audienc

Neamine dimers targeting the HIV-1 TAR RNA.

International audienc

Mechanism of RNA cleavage catalyzed by sequence specific polyamide nucleic acid-neamine conjugate.

International audienc

Synthesis of 1,2-cis-Homoiminosugars Derived from GlcNAc and GalNAc Exploiting a β-Amino Alcohol Skeletal Rearrangement

International audienceThe synthesis of 1,2-cis-homoiminosugars bearing an NHAc group at the C-2 position is described. The key step to prepare these a-d-GlcNAc and a-d-GalNAc mimics utilizes a beta-amino alcohol skeletal rearrangement applied to an azepane precursor. This strategy also allows access to naturally occurring a-HGJ and a-HNJ. The a-d-GlcNAc-configured iminosugar was coupled to a glucoside acceptor to yield a novel pseudodisaccharide. Preliminary glycosidase inhibition evaluation indicates that the a-d-GalNAc-configured homoiminosugar is a potent and selective a-N-acetylgalactosaminidase inhibitor

Six-monthly appointment spacing for clinical visits as a model for retention in HIV Care in Conakry-Guinea: a cohort study

Abstract Background The outbreak of the Ebola virus disease (EVD) in 2014 led to massive dropouts in HIV care in Guinea. Meanwhile, Médecins Sans Frontières (MSF) was implementing a six-monthly appointment spacing approach adapted locally as Rendez-vous de Six Mois (R6M) with an objective to improve retention in care. We sought to evaluate this innovative model of ART delivery in circumstances where access to healthcare is restricted. Methods A retrospective cohort study in 2014 of the outcome of a group of stable patients (viral load ≤1000 copies/μl) enrolled voluntarily in R6M compared with a group of stable patients continuing standard one to three monthly visits in Conakry. Log-rank test and Cox proportional hazards model were used to compare rates of attrition (deaths and defaulters) from care between the two groups. A linear regression analysis was used to describe the trend or pattern in the number of clinical visits over time. Results Included were 1957 adults of 15 years old and above of whom 1166 (59.6%) were enrolled in the R6M group and 791 (40.4%) in the standard care group. The proportion remaining in care at 18 months and beyond was 90% in the R6M group; significantly higher than the 75% observed in the control group (p < 0.0001). After adjusting for duration on ART and tuberculosis co-infection as covariates, the R6M strategy was associated with a 60% reduction in the rate of attrition from care compared with standard care (adjusted Hazard Ratio = 0.40, 95%CI: 0.27–0.59, p < 0.001). There was a negative secular trend in the number of monthly clinical visits for 24 months as the predicted caseload reduced on average by just below 50 visits per month (β = −48.6, R2 = 0.82, p < 0.0001). Conclusion R6M was likely to reduce staff workload and to mitigate attrition from ART care for stable patients in Conakry despite restricted access to healthcare caused by the devastating EVD on the health system in Guinea. R6M could be rolled out as the model of care for stable patients where and when feasible as a strategy likely to improve retention in HIV care

In silico analyses of essential interactions of iminosugars with the Hex A active site and evaluation of their pharmacological chaperone effects for Tay–Sachs disease

International audienc