Peptide Derivatives of Antibiotics Tylosin and Desmycosin, Protein Synthesis Inhibitors

Biologically active peptide derivatives of 16-member macrolide antibiotics were synthesized as potential probes for the investigation of nascent peptide chain topography in the ribosomal exit tunnel. The tylosin and desmycosin aldehyde groups at the C6 position of the lactone ring were modified by the aminooxyacetyl-L-alanyl-L-alanine methyl ester.     

Efficacy of Novel Antimicrobials Against Clinical Isolates of Opportunistic Amebas

ABSTRACT We examined the effects of the macrolide antimicrobial agent azithromycin and phenothiazine compounds against clinical isolates of Acanthamoeba spp. and Balamuthia mandrillaris , opportunistic pathogens of human beings and other animals. Acanthamoeba growth was inhibited in vitro at 1,5, and 10 μg/ml of azithromycin, but not the macrolides, erythromycin, and clarithromycin. In experiments attempting to simulate in vivo conditions, azithromycin protected monolayers of rat glioma cells from destruction by Acanthamoeba at a concentration of 0.1 μg/ml, and delayed destruction at concentrations of 0.001 and 0.01 μg/ml. We concluded that the minimal inhibitory concentration of azithromycin was 0.1 μg/ml. Our results, however, suggested that the drug was amebastatic but not amebicidal, since ameba growth eventually resumed after drug removal. The phenothiazines (chlorpromazine, chlorprothixene, and triflupromazine) inhibited Acanthamoeba growth by 70-90% at 5 and 10 μg/ml, but some of these compounds were toxic for rat glioma cells at 10 μg/ml. Azithromycin was not very effective against B. mandrillaris in an in vitro setting, but was amebastatic in tissue culture monolayers at concentrations of 0.1 μg/ml and higher. Balamuthia amebas showed in vitro sensitivity to phenothiazines. Ameba growth was inhibited 30-45% at 5 μg/ml in vitro, but completely at 5 μg/ml in the rat glioma model. In spite of their potential as antiamebic drugs in Balamuthia infections, toxicity of phenothiazines limits their use in clinical settings.     

Evolution and ecology of antibiotic resistance genes

A new perspective on the topic of antibiotic resistance is beginning to emerge based on a broader evolutionary and ecological understanding rather than from the traditional boundaries of clinical research of antibiotic-resistant bacterial pathogens. Phylogenetic insights into the evolution and diversity of several antibiotic resistance genes suggest that at least some of these genes have a long evolutionary history of diversification that began well before the 'antibiotic era'. Besides, there is no indication that lateral gene transfer from antibiotic-producing bacteria has played any significant role in shaping the pool of antibiotic resistance genes in clinically relevant and commensal bacteria. Most likely, the primary antibiotic resistance gene pool originated and diversified within the environmental bacterial communities, from which the genes were mobilized and penetrated into taxonomically and ecologically distant bacterial populations, including pathogens. Dissemination and penetration of antibiotic resistance genes from antibiotic producers were less significant and essentially limited to other high G+C bacteria. Besides direct selection by antibiotics, there is a number of other factors that may contribute to dissemination and maintenance of antibiotic resistance genes in bacterial populations.     

Computer-aided design of polyketides with the required properties

An approach to rational design of new polyketides with the required spectrum of biological activity has been proposed. We have developed the BioGenPharm software, which generates combinatorial libraries of polyketides based on the user-defined input parameters, performs prediction of biological activity spectra for the generated structures and selection of molecuels with the required properties. PASS algorithm has been applied for prediction of polyketide activity spectra (http://www.ibmc.msk.ru/PASS). Validation of PASS prediction ability for polyketides was performed vs. the evaluation set containing 242 natural macrolides from the Dictionary of Natural Products. The mean prediction accuracy was 75.5%. The problem of choice of the cutting points for probability of the presence of activity (Pa), which provides optimal combination of such parameters as sensitivity, specificity, concordance has been considered. Applicability of the described method has been illustrated by generation of a virtual library of the erythromycin analogues and selection of substances with low probability of the hepatotoxic effect.     

Effects of macrolides on airway microbiome and cytokine of children with bronchiolitis: A systematic review and meta‐analysis of randomized controlled trials

Macrolides may attenuate airway inflammation of bronchiolitis with anti‐inflammatory and antiviral effects. However, the potential mechanisms of action underlying the efficiency of macrolides in treating bronchiolitis are limited. Therefore, we performed a meta‐analysis to assess the effects of macrolides on airway microbiome and cytokine of children with bronchiolitis. PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched until May 2018. The reference lists of included studies and pertinent reviews were investigated for supplementing our search. Randomized controlled trials (RCTs) that compared macrolides with placebo assessing the change of microbiome in airway and cytokine were included. A total of four RCTs were included in this review. Data analysis showed no significant reduction of viruses at 48 hr after azithromycin treatment (p = 0.41). There were significant reductions in Streptococcus pneumoniae (risk ratio [RR] 0.28, 95% confidence interval (CI) 0.14 to 0.6, p < 0.01), Haemophilus influenza (RR 0.35, 95% CI 0.2 to 0.62, p < 0.01), and Moraxella catarrhalis (RR 0.29, 95% CI 0.17 to 0.5, p < 0.01), but no significant reduction of Staphylococcus aureus (p = 0.28) following treatment with macrolides. There was a significant decrease in the serum interleukin‐8(IL‐8), interleukin‐4(IL‐4), and eotaxin levels following 3 weeks of clarithromycin therapy. There was no significant difference in the serum IL‐8 level at Day 15 after the intervention between the azithromycin and control groups; however, a significant reduction of nasal lavage IL‐8 level was found. The macrolides may reduce the IL‐8 levels in the airway and plasma, but failed to demonstrate an antiviral effect in children with bronchiolitis.     

链霉菌KIB-H1556次级代谢产物抗植物真菌活性研究

对曼陀罗(Datura stramonium L.)根际链霉菌Streptomyces sp.KIB-H1556的次级代谢产物进行研究,利用硅胶柱色谱、凝胶柱色谱和半制备HPLC等分离手段对其发酵产物进行分离纯化,采用MS和NMR等波谱学手段并结合文献数据鉴定了3个单体化合物的结构,分别为:Bafilomycin D(1)、Bafilomycin B1(2)和Bafilomycin B2(3)。初步抗植物病原真菌活性筛选发现化合物2和3具有广谱抗真菌活性,尤其对玉米病原真菌的抑制活性显著,可作为玉米病原真菌病害的潜在生物防治剂。     

耐药大环内酯类肺炎支原体肺炎患儿外周血HMGB1表达与预后转归的关系

摘要 目的：探讨耐药大环内酯类肺炎支原体(Mycoplasma pneumoniae,MP)肺炎患儿外周血高迁移率族蛋白 B1(high mobility group protein B1,HMGB1)表达与预后转归的关系。方法：2017年1月-2019年12月选择在新疆维吾尔自治区人民医院诊治的耐药大环内酯类肺炎支原体肺炎患儿78例、非耐药大环内酯类肺炎支原体肺炎患儿78例与健康儿童78例分别作为耐药组、非耐药组与对照组,检测三组外周血HMGB1表达水平,调查耐药组患儿的急性生理与慢性健康(Acute Physiology and Chronic Health Evaluation,APACHEⅡ)评分与随访预后并进行相关性分析。结果：耐药组、非耐药组的血清HMGB1水平高于对照组(P<0.05),耐药组高于非耐药组(P<0.05)。随着入院时间的增加,耐药组患儿的APACHEⅡ评分逐渐降低,对比差异有统计学意义(P<0.05)。随访到2020年5月1日,耐药组患儿死亡2例,死亡率为2.6 %。在耐药组中,Pearson相关分析显示外周血HMGB1与APACHEⅡ评分、发热持续时间、住院时间、肺部病变个数存在相关性(P<0.05)。受试者工作特征(receiver operating characteristic,ROC)曲线分析显示外周血HMGB1、APACHEⅡ评分预测患儿死亡的最大截面积为0.872(95 %CI：0.729-0.878)和0.889(95 %CI：0.813-0.941)。结论：耐药大环内酯类肺炎支原体肺炎患儿外周血HMGB1呈现高表达状况,与患儿的APACHEⅡ评分呈现正相关性,以上结果有助于预测患儿的随访预后,并为进一步明确该病的发生机制提供一定的借鉴。     

Albocycline‐type Macrolides with Antibacterial Activities from Streptomyces sp. 4205

The actinomycete genus Streptomyces is characterized by producing bioactive secondary metabolites, including antibiotics. In this study, chemical and biological investigations were carried out on Streptomyces strain 4205 isolated from the paddy soil, leading to the identification and characterization of 10 albocycline‐type macrolides, among which 4 compounds were new, namely albocyclines A–D ( 1 – 4 ). The structures of 1 – 10 were identified according to the 1D‐ and 2D‐NMR spectroscopic data. Furthermore, compounds 1 – 10 were evaluated for antimicrobial activity. Compounds 5 – 7 displayed antimicrobial activities against Candidaalbicans ATCC 90028 with the same MIC value of 10.0 mg/mL and the IC₅₀ values of 1.5, 1.0, and 1.0 mg/mL, respectively. Thus, the research on Streptomyces sp. is of vital significance for developing new antibiotic agents.     

Novel Production of Isochainin by a Strain of <Emphasis Type="Italic">Streptomyces </Emphasis>sp<Emphasis Type="Italic">.</Emphasis> Isolated from Rhizosphere Soil of the Indigenous Moroccan Plant <Emphasis Type="Italic">Argania Spinosa</Emphasis> L

Summary An actinomycete strain (designated Ap1) isolated from the rhizosphere soil of Argania spinosa L. strongly inhibited the growth of two plant pathogens: Fusarium oxysporum f.sp. albedinis and Verticillium dahliae. The spore morphology suggested that the Ap1 strain belonged to the genus Streptomyces. The antifungal compound produced by Ap1 was purified by HPLC and identified as the polyene macrolide, isochainin, by NMR and mass spectroscopy. Ap1 showed normal biosynthesis of isochainin in comparison with S. cellulosae ATTC 12625, in which precursor-directed biosynthesis by feeding ethyl (Z)-16-phenylhexadec-9-enoate to the culture medium is required. In addition, Streptomyces sp. strain Ap1 produces isochainin with a 6.5-fold higher concentration than Streptomyces cellulosae ATTC 12625.