细胞分裂蛋白FtsZ抑制剂的研究进展

细菌耐药性问题日益严重,越来越多的致病菌对现有抗生素产生了耐药性.开发新靶点的抗生素迫在眉睫.FtsZ 是介导细菌细胞分裂的关键蛋白,由于与人类微管蛋白序列的差异,有可能设计选择性作用于细菌FtsZ而不干扰宿主细胞的抑制剂,FtsZ蛋白有希望成为抗菌药物研究的新靶点.本文从人类微管蛋白抑制剂、GTP类似物、天然产物和化合物库广筛等方面综述了以FtsZ为靶点的抗菌药物研究的最新进展.     

Antibacterial agents: patent highlights January to June 2002

A total of 48 patents dealing with disclosures on the different classes of antibacterial agents, including the beta-lactams, oxazolidinones, macrolides, quinolones, tetracyclines and miscellaneous antibacterial agents reported between January and June 2002 are selected for review. The miscellaneous agents section focused on the significant discovery of potential lead compounds as inhibitors of bacterial fatty acid synthase and peptide deformylase, and also included examples of novel peptidic antibiotics and pleuromutilin derivatives along with their antibacterial activities. Only a few patents disclosed novel agents in the quinolone and carbapenem areas. There are several patents disclosing improved formulation of old agents to increase their effectiveness and stability upon storage. Two patents disclosed effectiveness of antibiotic combinations with respect to the newer antibiotics linezolid and quinupristin/dalfopristin.     

Inhibition of RND-type efflux pumps confers the FtsZ-directed prodrug TXY436 with activity against Gram-negative bacteria

Infections caused by Gram-negative bacterial pathogens are often difficult to treat, with the emergence of multidrug-resistant strains further restricting clinical treatment options. As a result, there is an acute need for the development of new therapeutic agents active against Gram-negative bacteria. The bacterial protein FtsZ has recently been demonstrated to be a viable antibacterial target for treating infections caused by the Gram-positive bacteria Staphylococcus aureus in mouse model systems. Here, we investigate whether an FtsZ-directed prodrug (TXY436) that is effective against S. aureus can also target Gram-negative bacteria, such as Escherichia coli. We find that the conversion product of TXY436 (PC190723) can bind E. coli FtsZ and inhibit its polymerization/bundling in vitro. However, PC190723 is intrinsically inactive against wild-type E. coli, with this inactivity being derived from the actions of the efflux pump AcrAB. Mutations in E. coli AcrAB render the mutant bacteria susceptible to TXY436. We further show that chemical inhibition of AcrAB in E. coli, as well as its homologs in Klebsiella pneumoniae and Acinetobacter baumannii, confers all three Gram-negative pathogens with susceptibility to TXY436. We demonstrate that the activity of TXY436 against E. coli and K. pneumoniae is bactericidal in nature. Evidence for FtsZ-targeting and inhibition of cell division in Gram-negative bacteria by TXY436 is provided by the induction of a characteristic filamentous morphology when the efflux pump has been inhibited as well as by the lack of functional Z-rings upon TXY436 treatment.     

Novel FabH inhibitors: a patent and article literature review (2000 – 2012)

Introduction: The traditional antimicrobial chemotherapy drugs play their effects mostly via bacterial interference with in vivo amino acids, nucleotides, amino sugars and other small molecule synthesis, or interfering the biochemical processes of these small molecules to synthesize nucleic acids, peptidoglycan and other biological macromolecules. In recent years, enzymes with single function in bacterial fatty acid synthetase system have become the genome-driven novel antibacterial drug targets. Among inhibitors of these targets, FabH inhibitors are distinguished, for their target is different from that of existing antibiotics. Therefore, discovery of FabH inhibitors might be a potential orientation to overcome bacterial resistance.

Areas covered: This review summarized new patents and articles published on FabH inhibitors from 2000 to 2012.

Expert opinion: The review gives a brief understanding about the background and development in the area of FabH inhibitors that aims to solve the bacterial resistance problem. This review puts emphasis on some typical small molecules, which participate in the process of FabH inhibition. Overall, the research scopes of antibacterial agents are getting broad. Fatty acid synthase (FAS) pathway has been proved to be a promising target for the therapy. However, claim of novel antibacterial agents with more active and higher specificity is still continued.     

A tour of recent patent applications addressing antibacterial resistance

Despite the large number of antibacterial agents on the market today, the continual development of multi-drug resistance creates an ongoing demand for novel antibacterial agents. This review summarises patent applications published between January 1999 and March 2002 claiming novel antibacterial agents that may provide relief from infections due to resistant bacterial pathogens. Variations on existing drug classes continue to appear; these compounds, however, are outside the scope of this review. Instead, the focus is on novel (not yet on market) classes for which a considerable patent estate has been formed or around which a variety of research groups have sought patents.     

Peptide deformylase inhibitors: a survey of the patent literature

New antibiotics with new mechanisms of action are desperately needed, as clinically significant bacterial pathogens have not only acquired resistance to nearly all existing antibiotics, but also increasingly exhibit multi-drug resistance. Peptide deformylase (PDF), a highly conserved metalloproteinase, is an essential enzyme in the bacterial life cycle. It catalyses the removal of the terminal formyl group from the N-terminal methionine residue of the nascent bacterial polypeptide chain. Thus, inhibition of PDF, by interfering with the bacterial protein maturation process, is providing a promising new and exciting target for antibiotic therapeutic intervention without interfering with eukaryotic metabolism. Antibiotics based on PDF inhibition have the potential to provide the much needed antibacterial activity against most of the major drug-resistant pathogens and could play a significant role in the treatment of community-acquired upper respiratory tract infections. This review covers all the patenting activity in this field of research up to, and including, March 2005, and will focus on the more significant patents and patent applications.     

Metal nanobullets for multidrug resistant bacteria and biofilms

Infectious diseases were one of the major causes of mortality until now because drug-resistant bacteria have arisen under broad use and abuse of antibacterial drugs. These multidrug-resistant bacteria pose a major challenge to the effective control of bacterial infections and this threat has prompted the development of alternative strategies to treat bacterial diseases. Recently, use of metallic nanoparticles (NPs) as antibacterial agents is one of the promising strategies against bacterial drug resistance. This review first describes mechanisms of bacterial drug resistance and then focuses on the properties and applications of metallic NPs as antibiotic agents to deal with antibiotic-sensitive and -resistant bacteria. We also provide an overview of metallic NPs as bactericidal agents combating antibiotic-resistant bacteria and their potential in vivo toxicology for further drug development.     

New quinolone antibiotics: a survey of the literature from 2005 to 2010

Importance of the field: The quinolone class of antibacterial agents has a proven track record over the past several decades for the treatment of bacterial infections. Their unique mechanism of action and bactericidal properties make them attractive therapeutic agents.

Areas covered in this review: Significant research efforts continue to the present day in both academia and industry, which have provided a number of promising drug candidates for further development. This review examines quinolones that have been approved for market, entered into clinical trials or reported in the literature during 2005 – 2010.

What the reader will gain: The reader will be provided with background information on the quinolones as well as recent research findings that demonstrate the continued utility of the class as antibacterial agents. The review highlights a number of recently reported compounds of interest.

Take home message: Despite nearly 40 years of research, quinolones still provide new analogs of both scientific and clinical interest. Compounds that are active against antibiotic resistant strains including multiple drug-resistant Mycobacterium tuberculosis as well as compounds with improved pharmacokinetic and safety profiles are goals for current and future programs in this area.     

Pleuromutilin antibacterial agents: patent review 2001 – 2006

Derivatives of the naturally occurring pleuromutilin, of which certain analogs were successfully developed in veterinary medicine, have regained interest in the past few years as promising antibacterial agents with potential for human use. This review provides an overview of patents related to pleuromutilin derivatives during 2001 – 2006. Representative compounds along with their antibacterial activities are selected for this purpose, and a section focuses on pleuromutilins in clinical development and practice, in particular retapamulin. Most of the patents reveal the usefulness of different analogs as antibacterial agents effective against multi-drug-resistant organisms, whereas one patent disclosed the in vitro effectiveness of pleuromutilins against Helicobacter pylori. Few patents disclosed novel formulations, methods of preparation in order to improve efficacy, delivery, stability upon storage and synthesis of pleuromutilins.     

Update on carbohydrate-containing antibacterial agents

Background: Since the first known use of antibiotics > 2,500 years ago, a research field with immense importance for the welfare of mankind has been developed. After a decrease in interest in this topic by the end of the 20th century the occurrence of (poly-)resistant strains of bacteria induced a revival of antibiotics research. Health systems have been seeking viable and reliable solutions to this dangerous and expansive threat. Objective: This review will focus on carbohydrate-containing antibiotics and will give an outline of recently published novel isolated, semisynthetic as well as synthetic structures, their mechanism of action, if known, and the strategies for the design of compounds with potential by improved antibacterial properties. Methods: The literature between 2000 and 2008 was screened with main focus on recent examples of novel structures and strategies for the lead finding of exclusively antibacterial agents. Results/conclusion: With the explanation of the role of the carbohydrate moieties in the respective antibacterial agents together with better synthetic strategies in carbohydrate chemistry as well as improvements in assay development for high throughput screening methods, carbohydrate-containing antibiotics can be used for the finding of potential drug leads that contribute to the fight against infections and diseases caused by (resistant) bacterial pathogens.     

Targeting FtsZ for antibacterial therapy: a promising avenue

The widespread problem of bacterial resistance towards existing drugs and the paucity of effective drugs for the treatment of bacterial infections have prompted the scientific community to think about novel strategies for discovering new classes of antibacterial drugs. Target-based screening of inhibitory molecules has emerged as an important alternative for the development of potent antibacterials. FtsZ is a prokaryotic cytoskeleton protein, which plays an important role in bacterial cell division. It forms a highly dynamic Z-ring at the centre of the cell and recruits other accessory proteins, which are involved in bacterial cytokinesis. Here, we discuss the assembly dynamics of FtsZ and the key features that place it among the novel antibacterial drug targets. The recent progress in finding the inhibitors of functional properties of FtsZ and its interactions with other proteins, which has been enabled by advanced screening methods and structure-based design, are presented herein. Although there are significant challenges in the development of this new class of antibacterial drugs, nonetheless the therapeutic potential of FtsZ as a drug target is motivating researchers to find lead molecules with enhanced efficacy and reduced toxicity.     

多肽类抗菌剂研究进展

耐药菌的出现为抗生素的研发提出了严峻挑战,改造已知物以及发掘新型抗菌剂成为抗菌剂研发的两个主要途径。很多多肽类化合物都具有抗菌的活性,并且在针对耐药菌的新型抗菌剂的研发途径中有天然的优势。本文从生物合成的途径中核糖体的参与与否出发将多肽类抗菌剂分为非核糖体肽．多肽类抗生素和核糖体机制介导的抗菌肽两大类型,并对它们各自的代表药物,抗菌作用特点和研发现状作了综述。     

Antibacterial agents: patent highlights January to June 2003

This review presents an overview of 38 patents published between January and June 2003 on different classes of antibacterial agents. Patent disclosures on novel oxazolidinone and macrolide derivatives with strong antibacterial activity continue to dominate patent publications in recent years. A use patent of a linezolid formulation for ear infections in infants and pre-operative procedure is highlighted. Disclosures on novel dual action oxazolidinone-quinolone hybrids designed to overcome bacterial resistance and new macrolide derivatives with antimycobacterial activity are also presented. Patents on beta-lactam and quinolone antibiotics focus on the development of new processes and formulations to improve cost, purity and stability of existing agents in clinical use. Novel antibacterial agents (DNA polymerase and D-glutamate racemase inhibitors) as potential lead compounds are also presented.     

Antibacterial drug discovery in the post-genomics era

Antibacterial research has evolved dramatically over the past five decades. Early work relied on serendipity of finding drug-like molecules, usually natural products that had desirable antibacterial and nontoxic properties without regard to mechanism of action. In the past decade, however, significant technological advances in the fields of genomics, molecular biology, high-throughput screening, and structural biochemistry have led to a fundamentally new paradigm in the pursuit of novel antibacterial agents. The new methods promise to lead to the discovery of novel drug-target pairs that will be useful in the continuing battle against drug-resistant bacterial infections. This review describes this new paradigm, the technologies on which it is based, and the current status of this approach in drug discovery.     

FtsZ: a novel target for tuberculosis drug discovery

The emergence of multi-drug resistant Mycobacterium tuberculosis (Mtb) strains has made many of the currently available anti-TB drugs ineffective. Accordingly there is a pressing need to identify new drug targets. FtsZ, a bacterial tubulin homologue, is an essential cell division protein that polymerizes in a GTP-dependent manner, forming a highly dynamic cytokinetic ring, designated as the Z ring, at the septum site. Following recruitment of other cell division proteins, the Z ring contracts, resulting in closure of the septum and then formation of two daughter cells. Since inactivation of FtsZ or alteration of FtsZ assembly results in the inhibition of Z ring and septum formation, FtsZ is a very promising target for new antimicrobial drug development. This review describes the function and dynamic behaviors of FtsZ, its homology to tubulin, and recent development of FtsZ inhibitors as potential anti-TB agents.     

Intracellular targets of antibacterial peptides

The recent past witnessed a decrease in the number of new antibacterial compounds approved by the regulatory agencies and an almost complete lack of molecules killing bacteria by novel mechanisms of action. The broad spectrum antimicrobial agents currently on the market carry the potential, and indeed victims, of resistance developed against them. The need for new types of antimicrobial drugs coincides with the desire of developing lead molecules that act selectively on a single strain, or perhaps on a few closely related strains. Such selectivity would exclude the likelihood of the emergence of broad-range resistance. Intracellular bacterial targets most prevalently proteins needed for the life cycle of bacteria, carry the potential to be a resourceful target for a new family of antimicrobial compounds. Inhibition of proteinaceous functions requires stereospecificity, and a drug structurally similar to the target proteins themselves. Indeed, some antibacterial peptides show selective inhibition of intracellular targets. A few native peptides and their designed analogs appear to kill only a limited number of bacterial strains. Identification of the binding sites on the target proteins would allow the design of strain-specific antibacterial and antifungal peptides without the fear of development of common resistance to these agents.     

UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) inhibitors: a new class of antibacterial agents

The rapid increase of health-threatening infections by Gram-negative pathogens along with the emergence of multidrug-resistant bacterial strains demands the development of novel antibiotics directed against the previously unexploited targets. One of the promising targets in Gram-negative bacteria is the zinc-dependent metalloamidase, UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC). LpxC catalyzes the first committed, second overall step in the biosynthetic pathway of lipid A. Thus, research on LpxC inhibitors as antibacterial agents has become an attractive field in the development of the novel antibiotic therapy of Gram-negative bacteria. In this review, we will summarize the recent progress in the studies on the structure, catalytic mechanism and regulation of LpxC and the current development of LpxC inhibitors.     

Antibacterial agents: patent highlights January 2005 to June 2005

This review summarizes patents claiming novel antibacterial agents published between January and June 2005. A total of 50 patents covering beta-lactam antibiotics, beta-lactamase inhibitors, macrolide, oxazolidinone, quinolone and quinoline derivatives, and miscellaneous agents such as peptide deformylase inhibitors are selected for review. The majority of the patents disclosed the syntheses and biological activities of novel agents, and novel uses, improved chemical processes and formulations of known antibiotics. Details of a novel 2,3-dihydro-6-nitro-imidazo[2,1-b]oxazole derivative with excellent activity against Mycobacterium tuberculosis, among others, are also presented.     

Antibacterial agents: patent highlights July to December 2002

Forty-five patents dealing with disclosures on the different classes of antibacterial agents, reported between July and December 2002, are selected for review. Disclosures dealing with novel derivatives of known antibacterials (beta-lactam, oxazolidinone, macrolide, quinolone, tetracycline and peptide derivatives), development of new processes and formulations to improve cost, activity and stability are highlighted. In addition, patent disclosures on novel oxazolidinone derivatives with broad-spectrum activity extended against fastidious Gram-negative bacilli are highlighted in comparison to linezolid. Novel antibacterial agents (peptide-deformylase inhibitors) that could serve as potential lead compounds are also presented.     

Derivatives of aryl-4-guanidinomethylbenzoate and N-aryl-4-guanidinomethylbenzamide as new antibacterial agents： synthesis and bioactivity

AIM: The aim of the present study was to design, synthesize, and evaluate novel antibacterial agents, derivatives of aryl-4-guanidinomethylbenzoate and N-aryl-4-guanidinomethylbenzamide. METHODS: A total of 44 derivatives of aryl-4-guanidin-omethylbenzoate (series A) and N-aryl-4-guanidinomethylbenzamide (series B) were synthesized and their antibacterial activities were assessed in vitro against a variety of Gram-positive and Gram-negative bacteria by an agar dilution method. RESULTS: Twelve compounds showed potent bactericidal effects against a panel of Gram-positive germs, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), vancomycin-intermediate Staphylococcus aureus (VISA), and methicillin-resistant coagulase-negative staphylococci (MRCNS), with minimum inhibitory concentrations (MIC) ranging between 0.5 and 8 microg/mL, which were comparable to the MIC values of several marketed antibiotics. They exhibited weak or no activity on the Gram-negative bacteria tested. In addition, these compounds displayed high inhibitory activities towards oligopeptidase B of bacterial origin. CONCLUSION: In comparison with the previously reported MIC values of several known antibiotics, the derivatives of aryl-4-guanidinomethylbenzoate and N-aryl-4-guanidinomethylbenzamide showed comparable in vitro bactericidal activities against VRE and VISA as linezolid. Their growth inhibitory effects on MRSA were similar to vancomycin, but were less potent than linezolid and vancomycin against MRCNS. This class of compounds may have the potential to be developed into narrow spectrum antibacterial agents against certain drug-resistant strains of bacteria.