微生物降解喹诺酮类抗生素的研究进展

喹诺酮类抗生素是以4-喹诺酮为基本构型的人工合成的广谱抗生素。它能以细菌的脱氧核糖核酸(DNA)为靶，通过妨碍细菌内的DNA回旋酶，从而引起对细菌DNA的不可逆破坏，从而获得抗菌的效应。近些年，由于人们对其不规范的生产和使用，抗生素污染成为了重要的环境问题。大量科学研究结果证实，微生物降解是现阶段解决抗生素对环境污染的最理想方式。为进一步推动喹诺酮类抗生素生物降解的研究，本文概述了纯细菌、纯真菌、微生物菌群对喹诺酮类抗生素的降解，并进行比较，对喹诺酮类抗生素生物降解亟待解决的问题进行了讨论，为微生物降解喹诺酮类抗生素后续研究提供参考。     

二氯氟化苯应用及市场前景分析

二氯氟化苯目前多应用于合成广谱抗生素环丙氟哌酸。它是合成喹诺酮类抗菌剂的起始原料,其化学名称为2,4-二氯氟苯·环丙氟哌酸通过干扰DNA功能而导致细菌死亡,另外又能破坏细菌的细胞膜,是喹诺酮类抗菌药物中最新和最强的药物。具有药效高、耐交叉使用、广谱抗菌,无毒副作用,且不需皮试等优点,所以近年来得到了迅速的发展。     

2,4-二氯氟苯应用及市场分析

2,4-二氯氟苯,外观为无色透明油状液体。该品主要用于医药和农药的中间体,目前多应用于合成广谱抗生素环丙氟哌酸,是合成喹诺酮类抗菌剂的起始原料。环丙氟哌酸通过干扰DNA功能而导致细菌死亡,另外又能破坏细菌的细胞膜。它是喹诺酮类抗菌药物中最新和最强的药物,所以在近年来得到了迅速的发展。     

项目市场——项目选登

四氟苯甲酸是重要的医药中间体，用以合成第三代含氟喹诺酮药物，该种抗菌药物以其广谱，高效，低毒等优势成为世界医药行业的新贵，喹诺酮(4-Quinolones)，又称吡酮酸或毗啶酮酸，是一类较新的合成抗菌药物。     

帕珠沙星合成工艺与应用浅谈

帕珠沙星是由日本富山化学公司于2002年开发上市的新型喹诺酮类抗菌药，它是通过抑制细菌DNA促旋酶和拓扑异构酶Ⅳ发挥抗菌作用，对各种感染症均显示优良的临床效果，且对中枢神经系统方面的副作用较弱。由于喹诺酮类药物不易受质粒传导耐药性的影响，帕珠沙星与其他喹诺酮类的抗菌药物间无交叉耐药性，所以具有良好的研究开发价值。     

抗感染药物研究现状与发展趋势（一）

作用机理 喹诺酮类药物是原核生物DNA拓扑异构酶Ⅱ或Ⅳ（又称回旋酶）的选择性抑制剂。     

吡哌酸一季度需求同比增六成半

据统计，今年一季度的吡哌酸需求强劲，同比净增六成半以上． 吡哌酸为喹诺酮类抗菌药，通过作用于细菌DNA旋转酶，干扰细菌DNA的合成，从而导致细菌死亡，对革兰阴性杆菌如大肠埃希菌、肺炎克雷伯菌、产气肠杆菌等具抗菌作用，疗效显著且价格十分低廉．     

吡哌酸需求强劲

据统计，2007年一季度的吡哌酸需求强劲，同比净增六成半以上． 吡哌酸为喹诺酮类抗菌药，通过作用于细菌DNA旋转酶，干扰细菌DNA的合成，从而导致细菌死亡，对革兰阴性杆菌如大肠埃希菌、肺炎克雷伯菌、产气肠杆菌等具抗菌作用，疗效显著且价格十分低廉．     

2，4-二氯-5-氟苯甲酸的合成研究

含氢喹诺酮类药物是1979年问世的一类合成抗感染药物，其抗菌机理是选择性抑制细菌DNA四旋酶和拓扑异构酶Ⅳ，导致细菌DNA不能正常合成和修复，对革兰氏阳性和阴性细菌、衣原体、支原体以及结合分技杆菌具有广谱抗菌作用。由于它具有新颖的化学结构、独特的作用机制和具有抗菌谱广、高效、毒副作用小等特点，所以自开发以来，国内外围绕这类药物的研究相当活跃。迄今已开发出40多个品种，并有注射、口服外用的滴眼液和滴鼻液等多种剂型用于临床抗感染治疗。     

喹诺酮类药物的研究与应用进展

喹诺酮是多种活性药物分子的骨架结构,至今已有超过10000种喹诺酮类衍生物被报道。喹诺酮类衍生物具有抗菌、抗结核病、抗疟疾、抗病毒等生理活性,是药物开发的一大热点。本文综述喹诺酮类药物的研究进展,展望其发展前景,为进一步开发喹诺酮类药物提供参考。     

Dual Escherichia coli DNA Gyrase A and B Inhibitors with Antibacterial Activity

The emergence of multidrug-resistant bacteria is a global health threat necessitating the discovery of new antibacterials and novel strategies for fighting bacterial infections. We report first-in-class DNA gyrase B (GyrB) inhibitor/ciprofloxacin hybrids that display antibacterial activity against Escherichia coli. Whereas DNA gyrase ATPase inhibition experiments, DNA gyrase supercoiling assays, and in vitro antibacterial assays suggest binding of the hybrids to the E. coli GyrA and GyrB subunits, an interaction with the GyrA fluoroquinolone-binding site seems to be solely responsible for their antibacterial activity. Our results provide a foundation for a new concept of facilitating entry of nonpermeating GyrB inhibitors into bacteria by conjugation with ciprofloxacin, a highly permeable GyrA inhibitor. A hybrid molecule containing GyrA and GyrB inhibitor parts entering the bacterial cell would then elicit a strong antibacterial effect by inhibition of both the GyrA and GyrB subunits of DNA gyrase and potentially slow bacterial resistance development.     

Synthesis and Evaluation of N‐Phenylpyrrolamides as DNA Gyrase B Inhibitors

ATP‐competitive inhibitors of DNA gyrase and topoisomerase IV are among the most interesting classes of antibacterial drugs that are unrepresented in the antibacterial pipeline. We developed 32 new N‐phenylpyrrolamides and evaluated them against DNA gyrase and topoisomerase IV from E. coli and Staphylococcus aureus. Antibacterial activities were studied against Gram‐positive and Gram‐negative bacterial strains. The most potent compound displayed an IC₅₀ of 47 nm against E. coli DNA gyrase, and a minimum inhibitory concentration (MIC) of 12.5 μm against the Gram‐positive Enterococcus faecalis. Some compounds displayed good antibacterial activities against an efflux‐pump‐deficient E. coli strain (MIC=6.25 μm ) and against wild‐type E. coli in the presence of efflux pump inhibitor PAβN (MIC=3.13 μm ). Here we describe new findings regarding the structure–activity relationships of N‐phenylpyrrolamide DNA gyrase B inhibitors and investigate the factors that are important for the antibacterial activity of this class of compounds.     

Probing Bacterial Uptake of Glycosylated Ciprofloxacin Conjugates

Mono‐ and disaccharide‐functionalised conjugates of the fluoroquinolone antibiotic ciprofloxacin have been synthesised and used as chemical probes of the bacterial uptake of glycosylated ciprofloxacin. Their antimicrobial activities against a panel of clinically relevant bacteria were determined: the ability of these conjugates to inhibit their target DNA gyrase and to be transported into the bacteria was assessed by using in vivo and in vitro assays. The data suggest a lack of active uptake through sugar transporters and that although the addition of monosaccharides is compatible with the inhibition of DNA gyrase, the addition of a disaccharide results in a significant decrease in antimicrobial activity.     

Mechanism of binding of fluoroquinolones to the quinolone resistance-determining region of DNA gyrase: towards an understanding of the molecular basis of quinolone resistance

We have studied the bacterial resistance to fluoroquinolones that arises as a result of mutations in the DNA gyrase target protein. Although it is known that DNA gyrase is a target of quinolone antibacterial agents, the molecular details of the quinolone-gyrase interaction remain unclear. The mode of binding of ciprofloxacin, levofloxacin, and moxifloxacin to DNA gyrase was analyzed by means of docking calculations over the surface of the QRDR of GyrA. The analysis of these binding models allows study of the resistance mechanism associated with gyrA mutations more commonly found in E. coli fluoroquinolone-resistant strains at the atomic level. Asp87 was found to be critical in the binding of these fluoroquinolones because it interacts with the positively charged nitrogens in these bactericidal drugs. The role of the other most common mutations at amino acid codon Ser83 can be explained through the contacts that the side chain of this residue establishes with fluoroquinolone molecules. Finally, our results strongly suggest that, although Arg121 has never been found to be associated with fluoroquinolone resistance, this residue makes a pivotal contribution to the binding of the antibiotic to GyrA and to defining its position in the QRDR of the enzyme.     

Antibacterial Activity of Hexadecynoic Acid Isomers toward Clinical Isolates of Multidrug-Resistant Staphylococcus aureus

In the present study, the structural characteristics that impart antibacterial activity to C₁₆ alkynoic fatty acids (aFA) were further investigated. The syntheses of hexadecynoic acids (HDA) containing triple bonds at C-3, C-6, C-8, C-9, C-10, and C-12 were carried out in four steps and with an overall yield of 34–78%. In addition, HDA analogs containing a sulfur atom at either C-4 or C-5 were also prepared in 69–77% overall yields, respectively. Results from this study revealed that the triple bond at C-2 is pivotal for the antibacterial activity displayed by 2-HDA, while the farther the position of the triple bond from the carbonyl group, the lower its bactericidal activity against gram-positive bacteria, including clinical isolates of methicillin-resistant Staphylococcus aureus (CIMRSA) strains. The potential of 2-HDA as an antibacterial agent was also assessed in five CIMRSA strains that were resistant to Ciprofloxacin (Cipro) demonstrating that 2-HDA was the most effective treatment in inhibiting their growth when compared with either Cipro alone or equimolar combinations of Cipro and 2-HDA. Moreover, it was proved that the inhibition of S. aureus DNA gyrase can be linked to the antibacterial activity displayed by 2-HDA. Finally, it was determined that the ability of HDA analogs to form micelles can be linked to their decreased activity against gram-positive bacteria, since critical micellar concentrations (CMC) between 50 and 300 μg/mL were obtained.     

Synthesis and Antimicrobial Activity of Albicidin Derivatives with Variations of the Central Cyanoalanine Building Block

To investigate the pharmacophore regions of the antibiotic albicidin, derivatives with variations on the central amino acid were synthesized. Charged as well as uncharged residues were chosen to explore the influence of charge, chirality, and steric bulk. The bioactivity of the newly synthesized derivatives was determined by a microdilution technique to obtain minimum inhibitory concentrations (MIC) values. The compounds were also tested in a cell‐free system to obtain information about their ability to inhibit their primary target, DNA gyrase. It was then shown that derivatives with uncharged side chains retain antibacterial activity, whereas incorporation of charged amino acid residues decreases the antibacterial activity dramatically, possibly due to restricted cell penetration of these derivatives. From the newly synthesized derivatives, the threonine derivative shows the most promising results in both tests. The information will help to develop the features of albicidin toward more drug‐like structures.     

Quinoline Hydrazide/Hydrazone Derivatives: Recent Insights on Antibacterial Activity and Mechanism of Action

Antibiotics are becoming gradually ineffective due to drug resistance, leading to greater difficulty in the treatment of infectious diseases. Therefore, the development of new chemical entities with different mechanisms of action is essential in the fight against resistant microorganisms. Various studies have shown that quinoline hydrazide/hydrazone derivatives possess several biological activities, such as antimalarial, antitubercular, anticancer, anti-inflammatory, and antimicrobial. Among these activities, the antibacterial activity of quinoline hydrazide/hydrazone derivatives is noteworthy. The synthetic flexibility of the quinoline ring has led to the development of a wide range of structurally diverse quinoline hydrazide/hydrazone derivatives, which can act at various bacterial targets such as DNA gyrase, glucosamine-6-phosphate synthase, enoyl ACP reductase, and 3-ketoacyl ACP reductase. This review emphasizes the antibacterial potential of various reported quinoline hydrazide/hydrazone derivatives based on substitution in the quinoline ring. The antibacterial activity of various metal-quinoline hydrazide/hydrazone complexes is also discussed. The aim of this review is to assemble and scrutinize the latest reports in this promising area of drug development.     

纳米银的抗菌机理研究进展

纳米银因其高效、广谱、不易产生耐药性、安全性高等优点,成为当前抗菌材料的研究热点之一,但目前对纳米银的抗菌机理仍有不同的认识.本文首先综述了国内外纳米银抗菌机理的研究进展和主要成果,主要从影响细菌生活环境、破坏细菌的细胞壁和细胞膜、抑制DNA复制、抑制酶呼吸作用和抑制其他酶活性5个方面分析了纳米银的抗菌机理.并且纳米银的抗菌过程受多种因素影响,文中详细阐述了纳米银的尺寸分布、形貌以及稳定剂、活性氧、菌种和培养基等因素对纳米银抗菌性的影响.最后指出纳米银的抗菌过程复杂,进一步研究其具体作用方式和机理以及影响抗菌作用的主要因素都将有助于纳米银抗菌材料的广泛应用.     

Enrofloxacin—The Ruthless Killer of Eukaryotic Cells or the Last Hope in the Fight against Bacterial Infections?

Enrofloxacin is a compound that originates from a group of fluoroquinolones that is widely used in veterinary medicine as an antibacterial agent (this antibiotic is not approved for use as a drug in humans). It reveals strong antibiotic activity against both Gram-positive and Gram-negative bacteria, mainly due to the inhibition of bacterial gyrase and topoisomerase IV enzymatic actions. The high efficacy of this molecule has been demonstrated in the treatment of various animals on farms and other locations. However, the use of enrofloxacin causes severe adverse effects, including skeletal, reproductive, immune, and digestive disorders. In this review article, we present in detail and discuss the advantageous and disadvantageous properties of enrofloxacin, showing the benefits and risks of the use of this compound in veterinary medicine. Animal health and the environmental effects of this stable antibiotic (with half-life as long as 3–9 years in various natural environments) are analyzed, as are the interesting properties of this molecule that are expressed when present in complexes with metals. Recommendations for further research on enrofloxacin are also proposed.     

Design,Synthesis, in vitro and in silico Characterization of 2-Quinolone-L-alaninate-1,2,3-triazoles as Antimicrobial Agents

Due to the ever-increasing antimicrobial resistance there is an urgent need to continuously design and develop novel antimicrobial agents. Inspired by the broad antibacterial activities of various heterocyclic compounds such as 2-quinolone derivatives, we designed and synthesized new methyl-(2-oxo-1,2-dihydroquinolin-4-yl)-L-alaninate-1,2,3-triazole derivatives via 1,3-dipolar cycloaddition reaction of 1-propargyl-2-quinolone-L-alaninate with appropriate azide groups. The synthesized compounds were obtained in good yield ranging from 75 to 80 %. The chemical structures of these novel hybrid molecules were determined by spectroscopic methods and the antimicrobial activity of the compounds was investigated against both bacterial and fungal strains. The tested compounds showed significant antimicrobial activity and weak to moderate antifungal activity. Despite the evident similarity of the quinolone moiety of our compounds with fluoroquinolones, our compounds do not function by inhibiting DNA gyrase. Computational characterization of the compounds shows that they have attractive physicochemical and pharmacokinetic properties and could serve as templates for developing potential antimicrobial agents for clinical use.