Novel Nitro-Heteroaromatic Antimicrobial Agents for the Control and Eradication of Biofilm-Forming Bacteria

The synthesis and biological activity of several novel nitrothiazole, nitrobenzothiazole, and nitrofuran containing antimicrobial agents for the eradication of biofilm-forming Gram-negative and Gram-positive pathogens is described. Nitazoxanide (NTZ), nitrofurantoin, and furazolidone are commercial antimicrobials which were used as models to show how structural modification improved activity toward planktonic bacteria via minimum inhibitory concentration (MIC) assays and biofilms via minimum biofilm eradication concentration (MBEC) assays. Structure–activity relationship (SAR) studies illustrate the ways in which improvements have been made to the aforementioned antimicrobial agents. It is of particular interest in this regard that the introduction of a chloro substituent at the 5-position of NTZ (analog 1b) resulted in marked activity enhancement, as did the replacement of the 2-acetoxy substituent in the latter compound with a basic amine group (analog 7b). It is also of importance that analog 4a, which is a simple methacrylamide, displayed noteworthy activity against S. epidermidis biofilms. These lead compounds identified to have high activity towards biofilms provide promise as starting points in future pro-drug studies

Identification of Staphylococcus aureus Penicillin Binding Protein 4 (PBP4) Inhibitors

Methicillin-resistant Staphylococcus aureus (MRSA) is a global healthcare concern. Such resistance has historically been attributed to the acquisition of mecA (or mecC), which encodes an alternative penicillin binding protein, PBP2a, with low β-lactam affinity. However, recent studies have indicated that penicillin binding protein 4 (PBP4) is also a critical determinant of S. aureus methicillin resistance, particularly among community-acquired MRSA strains. Thus, PBP4 has been considered an intriguing therapeutic target as corresponding inhibitors may restore MRSA β-lactam susceptibility. In addition to its role in antibiotic resistance, PBP4 has also recently been shown to be required for S. aureus cortical bone osteocyte lacuno-canalicular network (OLCN) invasion and colonization, providing the organism with a niche for re-occurring bone infection. From these perspectives, the development of PBP4 inhibitors may have tremendous impact as agents that both reverse methicillin resistance and inhibit the organism’s ability to cause chronic osteomyelitis. Accordingly, using a whole-cell high-throughput screen of a 30,000-member small molecule chemical library and secondary assays we identified putative S. aureus PBP4 inhibitors. Quantitative reverse transcriptase mediated PCR and PBP4 binding assays revealed that hits could be further distinguished as compounds that reduce PBP4 expression versus compounds that are likely to affect the protein’s function. We also showed that 6.25 µM (2.5 µg/mL) of the lead candidate, 9314848, reverses the organism’s PBP4-dependent MRSA phenotype and inhibits its ability to traverse Microfluidic-Silicon Membrane-Canalicular Arrays (µSiM-CA) that model the OLCN orifice. Collectively, these molecules may represent promising potential as PBP4-inhibitors that can be further developed as adjuvants for the treatment of MRSA infections and/or osteomyelitis prophylactics

Soils are a non-negligible source of NO in a UK suburban greenspace and SE Australian Eucalyptus forest

Nitrogen oxides, particularly NO and NO2 (NOx), are primary air pollutants that also play an essential role in the atmospheric oxidation of volatile organic compounds, resulting in ozone and secondary organic aerosol formation. It is therefore critical to fully characterise NOx sources and sinks to understand tropospheric photochemistry and hence local- to regional-scale air quality. Human activities such as transport and power plants are well-known NOx emission sources in urban areas, whereas natural sources such as soils have been considered to contribute more substantially in rural and remote areas. However, soil NO emissions are poorly characterised and therefore underrepresented in models. To improve our understanding of soil as a source of NO, we measured diurnal patterns in soil NO concentrations at a suburban site in the UK and a remote field site in Australia to determine whether soils contribute to local atmospheric NO, and to identify the potential drivers of soil NO emissions. Mean soil NO concentrations in both UK campaigns 1.76 ± 0.92 ppb in summer and 0.91 ± 0.37 ppb in winter) were higher than those measured in Australia (0.73 ± 0.73 ppb). The diel patterns of NO concentrations (both sites) and emissions rates (Australia) showed a clear peak corresponding to local emission sources, but variation in NO was also related to either vapour pressure deficit (R2 = 0.88 in UK summer, R2 = 0.51 in Australia, both p \u3c 0.05) or solar radiation (R2 = 0.06 with p \u3e 0.4 in UK summer, R2 = 0.71 with p \u3c 0.05 in Australia) during the daylight hours, indicating biogenic origin of soil NO. Our work demonstrates that biogenic soil emissions of NO are non-negligible, estimated at around 1.32 % of total NO emissions at the remote site, and 0.22 % at the urban site, and must be accounted for in global and regional atmospheric chemistry-climate modelling and NOx reduction strategies

Advanced Glycation End Products as a Potential Target for Restructuring the Ovarian Cancer Microenvironment: A Pilot Study

Ovarian cancer is the sixth leading cause of cancer-related death in women, and both occurrence and mortality are increased in women over the age of 60. There are documented age-related changes in the ovarian cancer microenvironment that have been shown to create a permissive metastatic niche, including the formation of advanced glycation end products, or AGEs, that form crosslinks between collagen molecules. Small molecules that disrupt AGEs, known as AGE breakers, have been examined in other diseases, but their efficacy in ovarian cancer has not been evaluated. The goal of this pilot study is to target age-related changes in the tumor microenvironment with the long-term aim of improving response to therapy in older patients. Here, we show that AGE breakers have the potential to change the omental collagen structure and modulate the peritoneal immune landscape, suggesting a potential use for AGE breakers in the treatment of ovarian cancer

New Genetically Engineered Derivatives of Antibacterial Darobac-tins Underpin their Potential for Antibiotic Development

Biosynthetic engineering of bi–cyclic darobactins, which selectively seal the lateral gate of the outer membrane pro-tein BamA, lead to highly active analogues which are up to 128–fold more potent against critical and clinically relevant Gram–negative pathogens compared to their native counterparts. Because of their excellent antibacterial activity, darobactins represent one of the most promising new antibiotic classes of the last decades. Here we present a series of structure-driven biosynthetic modifications of our current frontrunner, darobactin 22 (D22), to investigate modifica-tions at the understudied positions 2, 4 and 5 of the darobactin heptapeptide for their impact on bioactivity. Novel darobactins were found highly active against critical pathogens from the WHO priority list. Antibacterial activity data were corroborated by determination of the dissociation constants KD with BamA beta barrel. The most promising de-rivatives, D22 and D69, were subjected to ADMET profiling, showing high metabolic and plasma stability and low plasma protein binding. We further evaluated D22 and D69 for bioactivity against multidrug–resistant clinical isolates and found them to have low to submicromolar activity

Advanced Glycation End Products as a Potential Target for Restructuring the Ovarian Cancer Microenvironment: A Pilot Study

Ovarian cancer is the sixth leading cause of cancer-related death in women, and both occurrence and mortality are increased in women over the age of 60. There are documented age-related changes in the ovarian cancer microenvironment that have been shown to create a permissive metastatic niche, including the formation of advanced glycation end products, or AGEs, that form crosslinks between collagen molecules. Small molecules that disrupt AGEs, known as AGE breakers, have been examined in other diseases, but their efficacy in ovarian cancer has not been evaluated. The goal of this pilot study is to target age-related changes in the tumor microenvironment with the long-term aim of improving response to therapy in older patients. Here, we show that AGE breakers have the potential to change the omental collagen structure and modulate the peritoneal immune landscape, suggesting a potential use for AGE breakers in the treatment of ovarian cancer.</p