Macrolones target bacterial ribosomes and DNA gyrase and can evade resistance mechanisms.

Growing resistance toward ribosome-targeting macrolide antibiotics has limited their clinical utility and urged the search for superior compounds. Macrolones are synthetic macrolide derivatives with a quinolone side chain, structurally similar to DNA topoisomerase-targeting fluoroquinolones. While macrolones show enhanced activity, their modes of action have remained unknown. Here, we present the first structures of ribosome-bound macrolones, showing that the macrolide part occupies the macrolide-binding site in the ribosomal exit tunnel, whereas the quinolone moiety establishes new interactions with the tunnel. Macrolones efficiently inhibit both the ribosome and DNA topoisomerase in vitro. However, in the cell, they target either the ribosome or DNA gyrase or concurrently both of them. In contrast to macrolide or fluoroquinolone antibiotics alone, dual-targeting macrolones are less prone to select resistant bacteria carrying target-site mutations or to activate inducible macrolide resistance genes. Furthermore, because some macrolones engage Erm-modified ribosomes, they retain activity even against strains with constitutive erm resistance genes.

Design and structure-activity relationships of ether-linked alkylides: Hybrids of 3-O-descladinosyl macrolides and quinolone motifs.

Ketolides (3-keto) such as TE-802 and acylides (3-O-acyl) like TEA0929 are ineffective against constitutively resistant pathogens harboring erythromycin ribosomal methylation (erm) genes. Following our previous work on alkylides (3-O-alkyl), we explored the structure-activity relationships of hybrids combining (R/S) 3-descladinosyl erythromycin with 6/7-quinolone motifs, featuring extended ether-linked spacers, with a focus on their efficacy against pathogens bearing constitutive erm gene resistance. Optimized compounds 17a and 31f not only reinstated efficacy against inducibly resistant pathogens but also demonstrated significantly augmented activities against constitutively resistant strains of Streptococcus pneumoniae and Streptococcus pyogenes, which are typically refractory to existing C-3 modified macrolides. Notably, hybrid 31f (coded ZN-51) represented a pioneering class of agents distinguished by its dual modes of action, with ribosomes as the primary target and topoisomerases as the secondary target. As a novel chemotype of macrolide-quinolone hybrids, alkylide 31f is a valuable addition to our armamentarium against macrolide-resistant bacteria.

Rationally Designed Novel Antimicrobial Peptides Targeting Chitin Synthase for Combating Soybean Phytophthora Blight.

Soybean phytophthora blight is a severe menace to global agriculture, causing annual losses surpassing USD 1 billion. Present crop loss mitigation strategies primarily rely on chemical pesticides and disease-resistant breeding, frequently surpassed by the pathogens' quick adaptive evolution. In this urgent scenario, our research delves into innovative antimicrobial peptides characterized by low drug resistance and environmental friendliness. Inhibiting chitin synthase gene activity in Phytophthora sojae impairs vital functions such as growth and sporulation, presenting an effective method to reduce its pathogenic impact. In our study, we screened 16 previously tested peptides to evaluate their antimicrobial effects against Phytophthora using structure-guided drug design, which involves molecular docking, saturation mutagenesis, molecular dynamics, and toxicity prediction. The in silico analysis identified AMP_04 with potential inhibitory activity against Phytophthora sojae's chitin synthase. Through three rounds of saturation mutagenesis, we pin-pointed the most effective triple mutant, TP (D10K, G11I, S14L). Molecular dynamic simulations revealed TP's stability in the chitin synthase-TP complex and its transmembrane mechanism, employing an all-atom force field. Our findings demonstrate the efficacy of TP in occupying the substrate-binding pocket and translocation catalytic channel. Effective inhibition of the chitin synthase enzyme can be achieved. Specifically, the triple mutant demonstrates enhanced antimicrobial potency and decreased toxicity relative to the wild-type AMP_04, utilizing a mechanism akin to the barrel-stave model during membrane translocation. Collectively, our study provides a new strategy that could be used as a potent antimicrobial agent in combatting soybean blight, contributing to sustainable agricultural practices.

Discovery of Novel Diphenyl Acrylonitrile Derivatives That Promote Adult Rats' Hippocampal Neurogenesis.

We previously discovered WS-6 as a new antidepressant in correlation to its function of stimulating neurogenesis. Herein, several different scaffolds (stilbene, 1,3-diphenyl 1-propene, 1,3-diphenyl 2-propene, 1,2-diphenyl acrylo-1-nitrile, 1,2-diphenyl acrylo-2-nitrile, 1,3-diphenyl trimethylamine), further varied through substitutions of twelve amide substituents plus the addition of a methylene unit and an inverted amide, were examined to elucidate the SARs for promoting adult rat neurogenesis. Most of the compounds could stimulate proliferation of progenitors, but just a few chemicals possessing a specific structural profile, exemplified by diphenyl acrylonitrile 29b, 32a, and 32b, showed better activity than the clinical drug NSI-189 in promoting newborn cells differentiation into mature neurons. The most potent diphenyl acrylonitrile 32b had an excellent brain AUC to plasma AUC ratio (B/P = 1.6), suggesting its potential for further development as a new lead.

Design and synthesis of novel macrolones bridged with linkers from 11,12-positions of macrolides.

Resistance to telithromycin and off-target effects associated with the metabolic instability present serious and challenging problems for the development of novel macrolides. Herein, studies of hybrids of macrolides and quinolones (termed macrolones) bridged with linkers from 11,12-cyclic carbamate of macrolides revealed different structure-activity relationships from the previously reported macrolones bridged with linkers derived from 6-, 9- and 4''-positions of macrolides. The optimized macrolone 34 g with a longer and rigid sidechain than telithromycin had improved metabolic stability compared to telithromycin (t1/2: 110 vs 32 min), whose future has been heavily clouded by metabolic issues. Moreover, 34 g was 38-fold more potent than telithromycin against A2058/2059-mutated Mycoplasma pneumoniae (8 vs 315 µM), which may be attributed to a novel mode of action between the carboxylic acid of quinolone moiety and the bacterial ribosome. This work increases the prospect for discovery of novel and safe antibacterial agents to combat serious human infectious diseases.

Design, synthesis and structure-bactericidal activity relationships of novel 9-oxime ketolides and reductive epimers of acylides.

Erythromycin was long viewed as a bacteriostatic agent. The erythromycin derivatives, 9-oxime ketolides have a species-specific bactericidal profile. Among them, the 3'-allyl version of the 9-oxime ketolide 1 (Ar=3-quinolyl; 17a) is bactericidal against Streptococcus pneumoniae and Streptococcus pyogenes. In contrast, the 2-fluoro analogs of 1, 13a (Ar=6-quinolyl), 13b (Ar=3-quinolyl) and 24a (Ar=4-isoquinolyl), show bactericidal activities against S. pneumoniae, Staphylococcus aureus and Moraxella catarrhalis, while the 2-fluoro analogs 13c (Ar=3-aminopyridyl) and 24b (Ar=3-carbamoylpyridyl) are only bactericidal against S. pneumoniae and Haemophilus influenzae. Reduction of the ketolides led to novel epiacylides, the 3-O-epimers of the acylides. Alteration of linker length (30b vs. 30a), 2-fluorination (33 vs. 30a) and incorporation of additional spacers at the 9-oxime or 6-OH (35, 40 vs. 30a) did not restore the epiacylides back to be as active as the acylide 31. Molecular docking suggested that epimerization at the 3-position reshapes the orientation of the 3-O-sidechain and leads to considerably weaker binding with bacterial ribosomes.

Comprehensive utilization of activated sludge for the preparation of hydrolytic enzymes, polyhydroxyalkanoates, and water-retaining organic fertilizer.

The urban wastewater treatment industry produces a large amount of excess activated sludge which is mainly composed of microbial biomass and costly to be disposed. In this research, a comprehensive utilization of activated sludge was developed by sequentially extracting hydrolytic enzymes and polyhydroxyalkanoates (PHAs), and the residue was used to prepare water-retaining organic fertilizer. The sludge was extracted with fourfold H2O-containing 1% Triton X-100 with the yield of 66.7% protease activity. The enzyme solution was precipitated in 80% acetone and vacuum dried at 40°C at the dried enzyme yield of 2.4 g/kg wet sludge. The enzyme product contains collagenase, lipase, amylase, and cellulase activities, which are good compound enzymes to feed. The PHAs were extracted with 30% sodium hypoclorite:chloroform (1:3). The PHA solution was decolored and dried, and pure white PHAs were obtained at the yield of 70.1 g/kg wet sludge. The residue was used to prepare water-retaining organic fertilizer at the optimal condition. The fertilizer absorbs 131.3-fold distilled water and had good performance in water retention and can effectively slow down the loss of soil moisture when added into soil. This work provides a simple and practical approach for comprehensive utilizing activated sludge with significant economic benefits.

[Advance in the study of compounds with potential activities in promotion of adult hippocampal neurogenesis].

With the increasing size of aging population all over the world, the incidence of Alzheimer's disease has reached to the highest level in many developed countries. However, the etiology of Alzheimer's disease remains largely unknown especially in the biological mechanism. Up to now, it is still a challenge that the disease can't be controlled by the approved clinical medicines. As a result, new therapeutic strategies are urgently needed to prevent and cure Alzheimer's disease. The hippocampus area is associated with learning, memory, cognitive regulation in the central nervous system, which is closely related to Alzheimer's disease. Adult neurogenesis in hippocampal area allows new neuronal cells to emerge in the central nervous system. The brain's plasticity is achieved in some sense. This review focuses on the progress in the study of variety of compounds in promotion of neurogenesis in adult hippocampal area in recent years. The potential of these compounds may shed a light on postponing the occurring of Alzheimer's disease or even curing it.

[Study of IR Property of Glow Discharge Polymer (GDP)].

To achieve the object of NIF ignition , it is required to prepare high density fuel targets . For DD layer, IR-layering can be used to improve its surface roughness. In this paper, glow discharge polymer (GDP) flat films and capsules were synthesized. The IR absorptive properties of GDP were thoroughly studied by using infrared spectrometer and microscopy while the extinction coefficients of GDP flat film at specific wavelengths were obtained. By comparing absorption properties of flat films and capsules, it is found that thermal treatments can lower the OH content of GDP and thus improve IR layering of DD ice. Finally, the needed IR power of integration sphere were estimated by using data obtained for future DD layering experiments in this paper. The results have laid a solid foundation for the implementation of DD IR layering.

Synthesis and structure-activity relationships of novel 9-oxime acylides with improved bactericidal activity.

9-Oxime acylides have different SAR and binding modes from 9-oxime ketolides. An aminopyridyl or carbamoylpyridyl group anchored at the end of the 9-oxime 2-propargyl group is beneficial for antimicrobial activity. Both the 2-pyridyl and 3-pyridyl groups derived from 3-OH have stacking interactions with the base pair G2505/C2610 (Escherichia coli numbering) of the bacterial rRNA. Compounds 3 presented characteristic features that belong to bactericidal agents when used against constitutive-erm resistant Staphylococcus aureus, susceptible and mef-encoded Streptococcus pneumoniae, inducible-erm resistant Streptococcus pyogenes, and Moraxella catarrhalis. A docking model indicated that the carbamoylpyridyl group of 3h may hydrogen bond to G2061 in addition to π-π stacking over the adenine of A2062 that proved to gate the tunnel for the egress of the nascent peptide. This study suggests that the 9-oxime acylides possess a bactericidal mechanism that is different from the traditional near-complete inhibition of protein synthesis. These studies provide a foundation for the rational design of macrolide antibiotics.

Design, synthesis and structure-activity relationships of novel non-ketolides: 9-Oxime clarithromycin featured with seven-to thirteen-atom-length diamine linkers at 3-OH.

We report here on the structure-activity relationships of hybrids combining 3-descladinosyl clarithromycin with quinolones linked by extended diamine connectors. Several hybrids, exemplified by 23Bc, 23Be, 23Bf, 26Be, and 30Bc, not only restored potency against inducibly resistant pathogens but also exhibited significantly enhanced activities against constitutively resistant strains of Staphylococcus pneumoniae and Staphylococcus pyogenes, which express high-level resistance independent of clarithromycin or erythromycin induction. Additionally, the novel hybrids showed susceptibility against Gram-negative Haemophilus influenzae. Notably, hybrid 23Be demonstrated dual modes of action by inhibiting both protein synthesis and DNA replication in vitro and in vivo. Given these promising characteristics, 23Be emerges as a potential candidate for the treatment of community-acquired bacterial pneumonia.

Discovery of a novel lead characterized by a stilbene-extended scaffold against sepsis as soluble epoxide hydrolase inhibitors.

Recently, some inhibitors of soluble epoxide hydrolase (sEH) showed limited potential in treating sepsis by increasing survival time, but they have unfortunately failed to improve survival rates. In this study, we initially identified a new hit 11D, belonging to a natural skeleton known as stilbene and having an IC50 of 644 nM on inhibiting murine sEH. Natural scaffold-based sEH inhibitors are paid less attention. A combination of structure-activity relationships (SARs)-guided structural optimization and computer-aided skeleton growth led to a highly effective lead compound 70P (IC50: 4.0 nM). The dose-response study indicated that 70P (at doses of 0.5-5 mg/kg, ip.) significantly increased survival rates and survival time by reducing the levels of the inflammatory factors TNF-α and IL-6 in the liver. Interestingly, 70P exhibited much higher accumulation in the liver than in plasma (AUC ratio: 175). In addition, 70P exhibits equal IC50 value (1.5 nM) on inhibiting human sEH as EC5026 (1.7 nM). In conclusion, the natural scaffold-extended sEH inhibitor 70P has the potential to become a new promising lead for addressing the unmet medical need in sepsis treatment, which highlighted the importance of natural skeleton in developing sEH inhibitors.

Synthetic macrolides overcoming MLSBK-resistant pathogens.

Conventional macrolide-lincosamide-streptogramin B-ketolide (MLSBK) antibiotics are unable to counter the growing challenge of antibiotic resistance that is conferred by the constitutive methylation of rRNA base A2058 or its G2058 mutation, while the presence of unmodified A2058 is crucial for high selectivity of traditional MLSBK in targeting pathogens over human cells. The absence of effective modes of action reinforces the prevailing belief that constitutively antibiotic-resistant Staphylococcus aureus remains impervious to existing macrolides including telithromycin. Here, we report the design and synthesis of a novel series of macrolides, featuring the strategic fusion of ketolide and quinolone moieties. Our effort led to the discovery of two potent compounds, MCX-219 and MCX-190, demonstrating enhanced antibacterial efficacy against a broad spectrum of formidable pathogens, including A2058-methylated Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and notably, the clinical Mycoplasma pneumoniae isolates harboring A2058G mutations which are implicated in the recent pneumonia outbreak in China. Mechanistic studies reveal that the modified quinolone moiety of MCX-190 establishes a distinctive secondary binding site within the nascent peptide exit tunnel. Structure-activity relationship analysis underscores the importance of this secondary binding, maintained by a sandwich-like π-π stacking interaction and a water-magnesium bridge, for effective engagement with A2058-methylated ribosomes rather than topoisomerases targeted by quinolone antibiotics. Our findings not only highlight MCX-219 and MCX-190 as promising candidates for next-generation MLSBK antibiotics to combat antibiotic resistance, but also pave the way for the future rational design of the class of MLSBK antibiotics, offering a strategic framework to overcome the challenges posed by escalating antibiotic resistance.

Synthesis and antibacterial activity of 9-oxime ether non-ketolides, and novel binding mode of alkylides with bacterial rRNA.

We report a series of new 9-oxime ether non-ketolides, including 3-hydroxyl, 3-O-acyl and 3-O-alkyl clarithromycin derivatives, and thiophene-containing ketolides 1b-1d. Unlike previously reported ketolide 1a, none of them is comparable to telithromycin. A molecular modeling study was performed to gain insight into the binding mode of alkylides 17-20 with bacterial rRNA and to rationalize the great disparity of their SAR. The 3-O-sidechains of 19 and 20 point to the so-called hydrophilic side of the macrolide ring, as seen in clarithromycin. In contrast, the 3-O-sidechains of 17 and 18 bend to the backside, the so-called hydrophobic side of the macrolide ring. The results clearly indicated the alkylides with improved antibacterial activity might possess a novel binding mode, which is different from clarithromycin and the alkylides with poor activity.

[Research on the quantitative analysis of D2 using Raman spectroscopy].

Raman spectroscopy was used for experimental research on D2 signal to noise ratio (SNR) under different conditions. The 32 mW Ar+ laser was injected into the Raman quartz glass cells to study the effect of grating, laser power, exposure time and the gas pressure on D2 Raman spectra SNR. D2 Raman spectral signal to noise ratio is proportional to the laser power, exposure time and gas pressure. The standard curve of the pressure and SNR for this experimental apparatus was obtained. Three sets of random samples were used to verify the formula SNR(J 2 --> 2) = 10.6 x 10(-4) p+1.271 34. When the deuterium pressure is 21 280 Pa, the relative error is 4.8%. When the pressure increases to 67 235 Pa, the relative error is down to 1.46%.

A Potential Strategy for Treatment of Neurodegenerative Disorders by Regulation of Adult Hippocampal Neurogenesis in Human Brain.

Adult hippocampal neurogenesis is a multistage mechanism that continues throughout the lifespan of human and non-human mammals. These adult-born neurons in the central nervous system (CNS) play a significant role in various hippocampus-dependent processes, including learning, mood regulation, pattern recognition, etc. Reduction of adult hippocampal neurogenesis, caused by multiple factors such as neurological disorders and aging, would impair neuronal proliferation and differentiation and result in memory loss. Accumulating studies have indicated that functional neuron impairment could be restored by promoting adult hippocampal neurogenesis. In this review, we summarized the small molecules that could efficiently promote the process of adult neurogenesis, particularly the agents that have the capacity of crossing the blood-brain barrier (BBB), and showed in vivo efficacy in mammalian brains. This may pave the way for the rational design of drugs to treat human neurodegenerative disorders in the future.

[Preliminary study on variations and neural generators of error-related negativity in first episode schizophrenics].

OBJECTIVE: To explore the variations and their activated brain areas of error-related negativity (ERN) in first episode schizophrenics. METHODS: ERN was tested by an ERP device and their activated brain areas were compared in 58 first episode schizophrenics (FES) and 62 normal controls (NC) from March 2010 to February 2011. RESULTS: (1) The ERN latencies in the FES group were significantly longer on Cz (58 ± 14 ms), Fz (60 ± 11 ms), C3 (57 ± 17 ms) and C4 (60 ± 13 ms) electrodes compared with those in the NC group (49 ± 13 ms, 47 ± 13 ms, 50 ± 14 ms, 51 ± 12 ms). And the ERN amplitudes were significantly lower than those in the controls in Cz (5.0 ± 2.8 µV; 7.5 ± 3.1 µV, P < 0.01), C3 (5.5 ± 4.0 µV; 8.0 ± 3.7 µV, P < 0.01), Fz (5.0 ± 3.1 µV; 7.7 ± 3.8 µV, P < 0.01) and Pz (4.5 ± 3.3 µV: 7.5 ± 3.0 µV, P < 0.01) electrodes.(2) The variations of ERN latencies and amplitudes showed an insignificant correlation with the positive symptom scores and total scores of PANSS. (3) The activation levels of insula, superior temporal gyrus, middle temporal gyrus and inferior parietal lobule were obviously lower in the FES group than those in the NC group. CONCLUSION: The anomalies of ERN latencies and amplitudes in first episode schizophrenics may reflect the deficient error-monitoring functions. Further studies are warranted. And such brain areas as insular may contribute pathogenically to the dysfunctions of error-monitoring in schizophrenics.

Synthesis and antibacterial activities of a novel alkylide: 3-O-(3-aryl-2-propargyl) and 3-O-(3-aryl-2-propenyl)clarithromycin derivatives.

A series of novel 3-O-(3-aryl-E-2-propenyl)clarithromycin derivatives 8 and 3-O-(3-aryl-2-propargyl)clarithromycin derivatives 11 were designed, synthesized, and evaluated for their in vitro antibacterial activities. Compared with 8c and 11c (Ar was 5-pyrimidyl), 3-O-(3-(5'-pyrimidyl)-Z-1-propenyl) counterpart 6c displayed 4- to 64-fold more potent activities against erythromycin-susceptible Staphylococcus aureus and Streptococcus pneumoniae. Moreover, the activities of 6c, 8c, and 11c against erythromycin-resistant S. aureus and S. pneumoniae were in general 4-fold higher than those of the reference compound, clarithromycin and azithromycin.

[The follow-up study on P50 auditory sensory gating in naïve schizophrenia].

OBJECTIVE: To understand the variations of sensory gating P50 in naïve schizophrenia during follow-up and the relations with positive and negative symptom scale (PANSS). METHODS: The data of auditory evoked potential P50 were recorded by USA Nicolet Brova instrument from 58 naïve schizophrenia patients (Sch) and 108 normal controls (NC) at baseline, Months 1, 2 and 3 after treatment. And a simultaneous assessment of PANSS was made. RESULTS: (1) At baseline, as compared with NC, Sch group had a sensory gating deficit, reflected by a higher S2/S1 (Cz: NC: 0.43 (0.27, 0.58); Sch: 0.77 (0.58, 1.04); Z = -9.23, P < 0.01), lower S1-S2 (Cz: NC: 2.65 (1.55, 4.79) microV; Sch: 0.92(-0.13, 2.32) microV; Z = -6.01, P < 0.01) and decreased more (1-S2/S1) (Cz: NC: 0.57 (0.43, 0.73); Sch: 0.23 (-0.04, 0.42); Z = -10.61, P < 0.01). (2) During follow-up, Sch group still had a sensory gating deficit. Compared with NC, Sch group had a more elevated S2-P50 amplitude, higher S2/S1, lower S1-S2 and (1-S2/S1) at Cz, Fz and Pz brain sites (P < 0.05 - 0.01), and no significantly differences with S2-P50 amplitude, S2/S1, S1-S2 and (1-S2/S1) during follow-up (P > 0.05). At baseline, Sch group had a much lowered S1-P50 amplitude than NC group at Cz and Fz brain sites (Cz: Sch: 4.1 microV +/- 2.1 microV, NC: 5.6 microV +/- 3.3 microV, t = -1.47, P = 0.001; Fz: Sch: 3.9 microV +/- 2.1 microV, NC: 5.6 microV +/- 3.9 microV, t = -1.63, P = 0.003). At Month 3, Sch group showed an improved S1-P50 amplitude to normal level at Cz brain site, but S1-P50 amplitude improved at Fz brain site but it was lower than NC group (Sch: 3.9 microV +/- 1.9 microV, NC: 5.6 microV +/- 3.9 microV, t = -1.62, P = 0.03). (3) At Month 3, Sch group showed a much lowered PANSS scale, positive symptom scale, negative symptom scale and general psychiatric symptoms scale than that at baseline (baseline: 138 +/- 15, 33 +/- 7, 41 +/- 5, 65 +/- 8; Month 3: 80 +/- 15, 17 +/- 4, 24 +/- 4, 38 +/- 9 respectively, P < 0.01). Spearman correlation revealed that P50 was not correlated with PANSS at baseline (P > 0.05). After treatment S2/S1 and (1-S2/S1) correlated with positive symptom scale and thought disorder and S1-S2 positively with thought disorder in schizophrenia (P < 0.05). CONCLUSION: Sensory gating deficit is closely related with thought disorder in naïve schizophrenia. And it may be an important pathogenesis of naïve schizophrenia. P50 sensory gating deficit is probably a diathesis marker in schizophrenia.

Design, synthesis and structure-activity relationships of novel 15-membered macrolides: Quinolone/quinoline-containing sidechains tethered to the C-6 position of azithromycin acylides.

In the search for novel hybrid molecules by fusing two biologically active scaffolds into one heteromeric chemotype, we found that hybrids of azithromycin and ciprofloxacin/gatifloxacin 26j and 26l can inhibit the supercoiling activity of E. coli gyrase by poisoning it in a way similar to fluoroquinolones. This may modestly contribute to their potencies, which are equal to ciprofloxacin against constitutively resistant Staphylococcus aureus, whose growth is not inhibited by the presence of macrolides. In contrast, introduction of quinolines (the 3-quinoline 26b and the 6-quinoline 26o) with an optimized rigid spacer at the 6-OH of azithromycin acylides did not exert significant potency against constitutively resistant S. aureus, despite the fact that the quinoline-containing compounds, exemplified by 26o, were as active as telithromycin against susceptible, inducibly- and efflux-resistant pathogens. The novel dual modes of action involving protein synthesis inhibition and poisoning DNA replication may pave the way for restoration of antibacterial activities of the current macrolides against constitutively resistant clinical isolates.