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β-Lactams are the most important class of antibiotics, for which the emergence of resistance threatens their utility. As such, we explored the extent to which the tetramic acid motif, frequently found in naturally occurring antibiotics, can be used to generate novel β-lactam antibiotics with improved antibacterial activity. We synthesized new ampicillin – tetramic acid, cephalosporin – tetramic acid, and cephamycin – tetramic acid analogs and evaluated their activities against problematic Gram-positive and Gram-negative pathogens. Amongst the analogs, a 7-aminocephalosporanic acid analog, 3397 , and a 7-amino-3-vinyl cephalosporanic acid, 3436 , showed potent activities against S. aureus NRS 70 (MRSA) with MICs of 6.25 μg/mL and 3.13 μg/mL respectively. These new analogs were ≥16-fold more potent than cefaclor and cephalexin. Additionally, a Δ 2 cephamycin – tetramic acid analog 3474 which contained a basic guanidinium substituent at the 5-position of the tetramic acid core displayed potent activity against several clinical strains of K. pneumoniae and E. coli . [ABSTRACT FROM AUTHOR]

The obligate intracellular parasite Chlamydia trachomatis has a reduced genome and is thought to rely on its mammalian host cell for nutrients. Although several lines of evidence suggests C. trachomatis utilizes host phospholipids, the bacterium encodes all the genes necessary for fatty acid and phospholipid synthesis found in free living Gram-negative bacteria. Bacterial-derived phospholipids significantly increased in infected HeLa cell cultures. These new phospholipids had a distinct molecular species composition consisting of saturated and branched-chain fatty acids. Biochemical analysis established the role of C. trachomatis-encoded acyltransferases in producing the new disaturated molecular species. There was no evidence for the remodeling of host phospholipids and no change in the size or molecular species composition of the phosphatidylcholine pool in infected HeLa cells. Host sphingomyelin was associated with C. trachomatis isolated by detergent extraction, but may represent contamination with detergent insoluble host lipids rather than being an integral bacterial membrane component. C. trachomatis assembles its membrane systems from the unique phospholipid molecular species produced by its own fatty acid and phospholipid biosynthetic machinery utilizing glucose, isoleucine and serine. [ABSTRACT FROM AUTHOR]

Abstract: PlsY is the essential first step in membrane phospholipid synthesis of Gram-positive pathogens. PlsY catalyzes the transfer of the fatty acid from acyl-phosphate to the 1-position of glycerol-3-phosphate to form the first intermediate in membrane biogenesis. A series of non-metabolizable, acyl-sulfamate analogs of the acyl-phosphate PlsY substrate were prepared and evaluated as inhibitors of Staphylococcus aureus PlsY and for their Gram-positive antibacterial activities. From this series phenyl (8-phenyloctanoyl) sulfamate had the best overall profile, selectively inhibiting S. aureus phospholipid biosynthesis and causing the accumulation of both long-chain fatty acids and acyl–acyl carrier protein intermediates demonstrating that PlsY was the primary cellular target. Bacillus anthracis was unique in being more potently inhibited by long chain acyl-sulfamates than other bacterial species. However, it is shown that Bacillus anthracis PlsY is not more sensitive to the acyl-sulfamates than S. aureus PlsY. Metabolic profiling showed that B. anthracis growth inhibition by the acyl-sulfamates was not specific for lipid synthesis illustrating that the amphipathic acyl-sulfamates can also have off-target effects in Gram-positive bacteria. Nonetheless, this study further advances PlsY as a druggable target for the development of novel antibacterial therapeutics, through the discovery and validation of the probe compound phenyl (8-phenyloctanoyl) sulfamate as a S. aureus PlsY inhibitor. [Copyright &y& Elsevier]

Abstract: A homology model of the p110α catalytic subunit of PI3Kα was generated from the p110γ crystal structure. Using this model, an isonicotinic scaffold was designed for chemically exploring the PI3Kα and γ binding sites. A focused library of derivatives was synthesized and tested. The morpholine acids 5a and 5b proved to be the most potent analogs. [Copyright &y& Elsevier]

Toxins TcdA and TcdB are the main virulence factors of Clostridioides difficile, a leading cause of hospital-acquired diarrhea. Despite their importance, there is a significant knowledge gap of druggable targets for inhibiting toxin production. To address this, we screened nonantibiotic phytochemicals to identify potential chemical genetic probes to discover antivirulence drug targets. This led to the identification of 18β-glycyrrhetinic acid (enoxolone), a licorice metabolite, as an inhibitor of TcdA and TcdB biosynthesis. Using affinity-based proteomics, potential targets were identified as ATP synthase subunit alpha (AtpA) and adenine deaminase (Ade, which catalyzes conversion of adenine to hypoxanthine in the purine salvage pathway). To validate these targets, a multifaceted approach was adopted. Gene silencing of ade and atpA inhibited toxin biosynthesis, while surface plasmon resonance and isothermal titration calorimetry molecular interaction analyses revealed direct binding of enoxolone to Ade. Metabolomics demonstrated enoxolone induced the accumulation of adenosine, while depleting hypoxanthine and ATP in C. difficile. Transcriptomics further revealed enoxolone dysregulated phosphate uptake genes, which correlated with reduced cellular phosphate levels. These findings suggest that enoxolone's cellular action is multitargeted. Accordingly, supplementation with both hypoxanthine and triethyl phosphate, a phosphate source, was required to fully restore toxin production in the presence of enoxolone. In conclusion, through the characterization of enoxolone, we identified promising antivirulence targets that interfere with nucleotide salvage and ATP synthesis, which may also block toxin biosynthesis. [ABSTRACT FROM AUTHOR]

• Use of GFRG building technology promotes the concept of industrial symbiosis. • Reduction in initial embodied energy due to GFRG building technology is determined. • Benefits of GFRG technology include savings on materials, time and manpower needs. • Significant reduction in self-weight of GFRG buildings and its related advantages. The present situation vis-á-vis increased energy use and environmental emissions has urged the building sector to contribute more towards sustainable construction. This is possible only through appropriate choice of building materials and technologies that minimize the environmental impacts. Nevertheless, the adoption of the same need to necessarily satisfy the user in terms of aesthetics, utility and cost. This paper presents the comparison of embodied energy of a two-storey residential building, made using, i) GFRG (glass fibre reinforced gypsum), and, ii) load-bearing brick masonry, building technologies. GFRG technology uses load-bearing walls and slabs that are manufactured using gypsum waste, and consumes reduced quantity of reinforced concrete in comparison with conventional construction. It has been found in this study that the embodied energy related to building materials of the GFRG building is 16% less, and that associated with transport of resources is twice, compared to the conventional brick masonry building. The major advantages of the GFRG building construction are found to be about – reduction in structural weight and construction cost, – savings in construction time and – savings in total man power requirement for construction. Further, the use of cement, steel rebar and sand is reduced by 25%, 36% and 44% respectively. [ABSTRACT FROM AUTHOR]

The bisphosphonates ((HO) 2 P(O)CR1R2P(O)(OH) 2 , BPs) were first shown to inhibit bone resorption in the 1960s, but it was not until 30 years later that a detailed molecular understanding of the relationship between their varied chemical structures and biological activity was elucidated. In the 1990s and 2000s, several potent bisphosphonates containing nitrogen in their R2 side chains (N-BPs) were approved for clinical use including alendronate, risedronate, ibandronate, and zoledronate. These are now mostly generic drugs and remain the leading therapies for several major bone-related diseases, including osteoporosis and skeletal-related events associated with bone metastases. The early development of chemistry in this area was largely empirical and only a few common structural features related to strong binding to calcium phosphate were clear. Attempts to further develop structure-activity relationships to explain more dramatic pharmacological differences in vivo at first appeared inconclusive, and evidence for mechanisms underlying cellular effects on osteoclasts and macrophages only emerged after many years of research. The breakthrough came when the intracellular actions on the osteoclast were first shown for the simpler bisphosphonates, via the in vivo formation of P-C-P derivatives of ATP. The synthesis and biological evaluation of a large number of nitrogen-containing bisphosphonates in the 1980s and 1990s led to the key discovery that the antiresorptive effects of these more complex analogs on osteoclasts result mostly from their potency as inhibitors of the enzyme farnesyl diphosphate synthase (FDPS/FPPS). This key branch-point enzyme in the mevalonate pathway of cholesterol biosynthesis is important for the generation of isoprenoid lipids that are utilized for the post-translational modification of small GTP-binding proteins essential for osteoclast function. Since then, it has become even more clear that the overall pharmacological effects of individual bisphosphonates on bone depend upon two key properties: the affinity for bone mineral and inhibitory effects on biochemical targets within bone cells, in particular FDPS. Detailed enzyme–ligand crystal structure analysis began in the early 2000s and advances in our understanding of the structure-activity relationships, based on interactions with this target within the mevalonate pathway and related enzymes in osteoclasts and other cells have continued to be the focus of research efforts to this day. In addition, while many members of the bisphosphonate drug class share common properties, now it is more clear that chemical modifications to create variations in these properties may allow customization of BPs for different uses. Thus, as the appreciation for new potential opportunities with this drug class grows, new chemistry to allow ready access to an ever-widening variety of bisphosphonates continues to be developed. Potential new uses of the calcium phosphate binding mechanism of bisphosphonates for the targeting of other drugs to the skeleton, and effects discovered on other cellular targets, even at non-skeletal sites, continue to intrigue scientists in this research field. • The structure-activity relationships of bisphosphonates are now well understood. • We review recent crystallographic studies of interactions of BPs and FDPS/GGPPS/SQS. • The actions and potential uses of BPs now extend to non-skeletal tissues. • Fluorescent BPs are useful tools for imaging bone and other tissues. • There is increasing success in using BPs to selectively target drugs to bone. [ABSTRACT FROM AUTHOR]

Studies of the potential role of bisphosphonates in dentistry date back to physical chemical research in the 1960s, and the genesis of the discovery of bisphosphonate pharmacology in part can be linked to some of this work. Since that time, parallel research on the effects of bisphosphonates on bone metabolism continued, while efforts in the dental field included studies of bisphosphonate effects on dental calculus, caries, and alveolar bone loss. While some utility of this drug class in the dental field was identified, leading to their experimental use in various dentrifice formulations and in some dental applications clinically, adverse effects of bisphosphonates in the jaws have also received attention. Most recently, certain bisphosphonates, particularly those with strong bone targeting properties, but limited biochemical effects (low potency bisphosphonates), are being studied as a local remedy for the concerns of adverse effects associated with other more potent members of this drug class. Additionally, low potency bisphosphonate analogs are under study as vectors to target active drugs to the mineral surfaces of the jawbones. These latter efforts have been devised for the prevention and treatment of oral problems, such as infections associated with oral surgery and implants. Advances in the utility and mechanistic understanding of the bisphosphonate class may enable additional oral therapeutic options for the management of multiple aspects of dental health. • The medical uses of bisphosphonates have shared origins from studies of their dental applications. • Bisphosphonates, when used at osteoporosis doses, do not block alveolar bone loss associated with periodontitis. • Osteonecrosis of the jaw (ONJ) is rare in BP-treated osteoporosis patients but common in oncology patients treated with BP therapy. • Novel ways of preventing and treating ONJ are under study. • Experimental studies show that BPs can potentially be used to deliver antibiotics to treat bone biofilm infections. [ABSTRACT FROM AUTHOR]