噁唑烷酮类抗菌药物构效关系新进展

综述新型抗菌药物噁唑烷酮类化合物近几年来的构效关系研究新进展，重点讨论母环上3位和5位的结构改造，噁唑烷酮3位氮原子接-苯环，苯环的对位为杂环取代，5位为乙酰胺甲基、硫代乙酰胺甲基、异噁唑氧甲基等，这些改造所得的化合物大都有良好的抗G^ 菌活性。     

Cadazolid: A new hope in the treatment of Clostridium difficile infection

Clostridium difficile infection (CDI) is a potential life-threatening consequence of antibiotic therapy. Although the risk increases with duration of treatment, it can also occur after a short treatment course. In addition to broad-spectrum antibiotics, anti-neoplastic agents, proton pump inhibitors, H² blockers, and several other drugs have been reported to induce intestinal dysbiosis, which is central to the pathogenesis of CDI. There is an increase in incidence and mortality attributed to CDI globally. Moreover, the epidemiology of C. difficile-associated diseases has changed significantly with an increasing occurrence of community-acquired CDI. Metronidazole and oral vancomycin are the first-line antibiotics used to treat CDI. However, metronidazole has limited effectiveness in severe cases and vancomycin use is associated with increasing risk of vancomycin resistance among Enterococcus spp. Cadazolid, a novel oxazolidinone antibiotic, has recently shown potent antimicrobial activity against C. difficile and has a lower propensity to induce resistance. The implications of its use in treating CDI have been reviewed based on current evidence.     

Novel Oxazolidinone Antibacterial Analogues with a Substituted Ligustrazine C‐ring Unit

A series of novel oxazolidinone compounds with a substituted ligustrazine C‐ring unit and different substituted groups at the C‐5 side chain were designed and synthesized using linezolid as a lead and based on a scaffold hopping strategy. Their antibacterial and anti‐inflammatory activities were evaluated. The results of in vitro antibacterial assays showed that all fourteen target compounds displayed potent activity against Gram‐positive pathogens, particularly 8b , 13b , 14a , 14b , 15a, and 15b . Moreover, 14a and 14b exhibited significant inhibitory activities on the production of inflammatory mediators, including nitric oxide, interleukin‐6, and tumor necrosis factor‐alpha. Thus, these derivatives could serve as valuable candidates to develop anti‐infective agents for the treatment of chronic wounds.     

7-{4-［2-［2-取代-4-((5S)-5-乙酰胺甲基-2-氧代-噁唑烷-3-基)苯基］乙基］哌嗪-1-基}-氟喹诺酮类化合物的合成与抗菌活性

目的寻找新型的噁唑烷酮-氟喹诺酮类抗菌药物。方法设计合成了7-{4-［2-［2-取代-4-((5S)-5-乙酰胺甲基-2-氧代-噁唑烷-3-基)苯基］乙基］哌嗪-1-基}-氟喹诺酮类化合物，测定其体外抗菌活性。结果共合成20个目标化合物，经^{1H NMR和MS确证结构。目标化合物具有较好的体外抗菌活性，尤其是化合物22，对屎肠球菌的抑制活性分别是吗啉噁酮和诺氟沙星的16倍和64倍，对金葡菌的抑制活性为吗啉噁酮的4倍。结论某些带有氟喹诺酮结构片段的噁唑烷酮类化合物抗菌活性加强。}     

Synthesis and in vitro evaluation of substituted phenyl-piperazinyl-phenyl oxazolidinones against Gram-positive bacteria

With the incidence of linezolid-resistant Enterococcus faecalis, E. faecium and Staphylococcus aureus, modification of linezolid at the 5- and/or 3-positions led to the development of a series of 3-(methoxyl-phenyl)-piperazinyl-phenyl oxazolidinone analogues. These compounds were tested in vitro against six gram-positive standard organisms (S. aureus, S. epidermidis, S. pneumoniae, S. albus, Streptococcus enteridis and S. nonhemolyticus). 5-acetylaminomethyl oxazolidinones bearing fluorine at 3'-position of phenyl ring showed activities against several gram-positive bacteria (MIC: 3.13-6.25 mug/mL). The position of methoxyl group on the phenyl ring of piperazine group affected antibacterial spectrum. 3-(4'- (para-methoxyl-phenyl)-piperazinyl)-(3'-fluoro)-phenyl-5-acetylaminomethyl oxazolidinone was found active against 5 gram-positive organisms except S. nonhemolyticus, whereas 3-(4'-(ortho-methoxyl-phenyl)-piperazinyl)-(3'-fluoro)-phenyl-5-acetylaminomethyl oxazolidinone was found active only against 2 gram-positive organisms, namely S. albus, S. enteridis.     

利奈唑胺在儿科应用研究进展

利奈唑胺（linezolid）是第一个临床应用的新型唑烷酮类抗生素,通过抑制细菌蛋白质的合成达到抑菌的作用。因利奈唑胺独特的作用位点和方式,故不易与其他基于抑制蛋白合成发挥抗菌作用的药物发生交叉耐药,而本身也不易诱导产生耐药性,其临床疗效已经得到一系列III期临床研究证明。现就其作用机制、儿科临床应用及不良反应进行综述。     

Recent developments in reversing glycopeptide-resistant pathogens

Recent studies addressing vancomycin-resistance phenomena are surveyed. Besides leading semi-synthetic glycopeptides: BI-397 and LY 333328, other new synthetic derivatives are also presented. Rational design based on the known mode of action is seen in recent research from both industrial and academic groups. Thus, Biosearch Italia SpA worked on new synthetic glycopeptides with a modified binding pocket in order to find drugs active against both vancomycin-sensitive and -resistant strains. Eli Lilly & Co. and research groups at Stanford, Cambridge and Harvard synthesised covalently linked dimers in order to copy the dimerisation and membrane anchoring effects. Both directions proved to be rewarding and some interesting compounds with potent in vitro activity against vancomycin-resistant enterococci (VRE) were found from these investigations. A new mechanistic proposal that can account for the bioactivity of LY 333328 against VRE was summarised. Research on new agents with modes of action different to that of glycopeptide antibiotics have also been successful and recent investigations related to RP-59500, SCH-27899 and U-100766 are presented.     

New anti-tuberculosis therapies

Tuberculosis (TB) is one of the most important global health problems in today's world. Poverty, inadequate health services, drug resistance and HIV/AIDS epidemic has hampered TB control, mostly in the developing nations, despite the worldwide availability of rifampicin-containing regimens with high antimycobacterial efficacy. Pharmaceutical companies have neglected the development of new anti-TB drugs in the last decades due to a lack of market incentives, while the public sector held only a meagre interest on TB control. However, novel initiatives, especially those merging in the Global Alliance for TB Drug Development, a public–private non-profit organisation backed by the World Health Organization, and a renewed interest in the research on Mycobacterium tuberculosis, have changed the TB pipeline in the last few years. At present, an unexpected number of new compounds are being developed in order to launch shorter and more efficient anti-TB therapies. This is the most active pipeline for TB drug development in known history.     

Novel agents for the treatment of resistant Gram-positive infections

Bacteria have proved themselves able to develop resistance to every antibiotic used clinically. Traditional agents used for treatment of serious infections caused by Gram-positive species have recently been supplemented with the introduction of linezolid, quinupristin-dalfopristin, several new quinolones and telithromycin. However, resistance to many of these agents has already been reported and, although each currently retains activity against the vast majority of clinical isolates of its target species, their long-term efficacy is uncertain. We must look to develop other compounds to replace and hopefully improve upon existing anti-Gram-positive agents. Daptomycin (a lipopeptide), oritavancin and dalbavancin (both second-generation glycopeptides) and ramoplanin (a glycolipodepsipeptide) are among the agents in advanced stages of development and, at present, many seem likely to proceed to licensing. In addition, it is encouraging that many agents active against novel bacterial targets have been discovered and are in earlier stages of development. In the next two decades, we should be optimistic that a regular flow of new anti-Gram-positive agents will enable us to offset the constant spectre of bacterial resistance.     

Novel antibacterial agents for the treatment of serious Gram-positive infections

With the continuing development of clinical drug resistance among bacteria and the advent of resistance to the recently released agents quinupristin-dalfopristin and linezolid, the need for new, effective agents to treat multi-drug-resistant Gram-positive infections remains important. This review focuses on agents presently in clinical development for the treatment of serious multidrug-resistant staphylococcal, enterococcal and pneumococcal infections, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci and penicillin-resistant Streptococcus pneumoniae. Agents to be discussed that affect the prokaryotic cell wall include the antimethicillin-resistant S. aureus cephalosporins BAL9141 and RWJ-54428, the glycopeptides oritavancin and dalbavancin and the lipopeptide daptomycin. Topoisomerase inhibitors include the fluoroquinolones gemifloxacin, sitafloxacin and garenoxacin. Protein synthesis inhibitors are represented by the ketolides telithromycin and cethromycin, the oxazolidinones and the glycylcycline tigecycline. Although each of these compounds has demonstrated antibacterial activity against antibiotic-resistant pathogens, their final regulatory approval will depend on an acceptable clinical safety profile.