烯二炔类抗肿瘤抗生素及其靶向药物研究近况

烯二炔类抗生素是一种结构新颖、作用机制独特的新型抗肿瘤抗生素,烯二炔结构是其活性中心。该类抗生素具有极强的抗肿瘤活性,却因毒性较大难以直接用于临床。近年来,研究人员展开了烯二炔类抗生素靶向药物的研发工作,以提高其肿瘤靶向性并减少药物毒副作用。归纳总结了已报道的天然来源的烯二炔类抗肿瘤抗生素及其活性代谢物,并重点介绍烯二炔类抗生素相关靶向药物的研究进展,旨在为其深度开发提供参考。     

Mammalian antibiotic peptides

The increasing development of bacterial resistance to traditional antibiotics has reached alarming levels, thus creating a strong need to develop new antimicrobial agents. These new antibiotics should possess novel mechanisms of action and different cellular targets compared with existing antimicrobials. Recent discoveries and isolations of so-called animal antibiotics, mostly small cationic peptides, which represent a potent branch of natural immunity, offered the possibility to acquire new and effective antibiotics of this provenance. To this date, more than 500 antibiotic peptides have been distinguished and defined. Their antimicrobial properties present new opportunities for their use as antibiotics or for construction of their more effective derivatives, but much research is still required to pave the way to their practical use. This is a survey of substances forming an armamentarium of natural immunity of mammals.     

Novel properties of antimicrobial peptides

Endogenous peptide antibiotics are known as evolutionarily old components of innate immunity. Due to interaction with cell membrane these peptides cause permeabilization of the membrane and lysis of invading microbes. However, some studies proved that antimicrobial peptides are universal multifunctional molecules and their functions extend far beyond simple antibiotics. In this review we present an overview of the general mechanism of action of antimicrobial peptides and discuss some of their additional properties, like antitumour activity, mitogenic activity, role in signal transduction pathways and adaptive immune response.     

The PASTA domain: a β-lactam-binding domain

The PASTA domain (for penicillin-binding protein and serine/threonine kinase associated domain) is found in the high molecular weight penicillin-binding proteins and eukaryotic-like serine/threonine kinases of a range of pathogens. We describe this previously uncharacterized domain and infer that it binds β-lactam antibiotics and their peptidoglycan analogues. We postulate that PknB-like kinases are key regulators of cell-wall biosynthesis. The essential function of these enzymes suggests an additional pathway for the action of β-lactam antibiotics.     

The PASTA domain: a beta-lactam-binding domain

The PASTA domain (for penicillin-binding protein and serine/threonine kinase associated domain) is found in the high molecular weight penicillin-binding proteins and eukaryotic-like serine/threonine kinases of a range of pathogens. We describe this previously uncharacterized domain and infer that it binds beta-lactam antibiotics and their peptidoglycan analogues. We postulate that PknB-like kinases are key regulators of cell-wall biosynthesis. The essential function of these enzymes suggests an additional pathway for the action of beta-lactam antibiotics.     

Use of sensitivity to antibiotics produced by representatives of the genera Williopsis and Zygowilliopsis in the identification of yeasts

Yeast strains belonging to the genera Candida and Hansenula were shown to differ in their susceptibility to the action of protein antibiotics produced by the yeasts Williopsis and Zygowilliopsis. This finding can be used as an additional criterion for yeast identification.     

Antibiotic Use in Animal Agriculture: What Have We Learned and Where are We Going?

Antibiotics are enormously important for the humane and efficient production of food animals. These benefits are somewhat offset by the human and animal health antibiotic resistance risks posed by their use in animals. This article provides an overview of what we have learned about antibiotic resistance as an issue in animal agriculture and where that knowledge could lead us in the future. To preserve the effectiveness of antibiotics, more action is needed to ensure their prudent use, particularly in the case of antibiotic growth promoters and antibiotics deemed critically important for human and animal health.     

Antibiotic use in animal agriculture: what have we learned and where are we going?

Antibiotics are enormously important for the humane and efficient production of food animals. These benefits are somewhat offset by the human and animal health antibiotic resistance risks posed by their use in animals. This article provides an overview of what we have learned about antibiotic resistance as an issue in animal agriculture and where that knowledge could lead us in the future. To preserve the effectiveness of antibiotics, more action is needed to ensure their prudent use, particularly in the case of antibiotic growth promoters and antibiotics deemed critically important for human and animal health.     

A Screening Procedure on the Inhibitors of Substrate-incorporation in Tumor Cells Methodological Survey and Its Evaluation

A comparative study of inhibition on the substrate-incorporation in several species of tumor cells has been achieved in combination with the antibiotics having different action mechanisms. It was thus revealed that a large part of the antitumor antibiotics so far examined showed a marked inhibitory response even at a low concentration. Particularly, the antibiotics whose action mechanism were established primarily on cell membrane were markedly sensitive. An apparent difference in the sensitivity was observed in some groups of antitumor antibiotics which act on nucleic acid synthesis. A methodological survey together with an evaluation of this procedure is discussed.     

Bacterial type II topoisomerases as targets for antibacterial drugs

Bacterial type II DNA topoisomerases are essential enzymes for correct genome functioning and cell growth. Gyrase is responsible for maintaining negative supercoiling of bacterial chromosome, whereas topoisomerase IV acts in disentangling daughter chromosomes following replication. Type II DNA topoisomerases possess an ATP binding site, which can be treated as a target for antibacterial drugs. Resolving crystal structures of protein fragments consisting of an ATP binding site complexed with ADPNP/antibiotics have proven to be valuable for the understanding of the mode of action of existing antibacterial agents and presented new possibilities for novel drug design. Coumarins, quinolones and cyclothialidines are diverse group of antibiotics that interfere with type II DNA topoisomerases, however their mode of action is different. Recently a new class of antibiotics, simociclinones, was characterized. Their mechanism of action towards gyrase is entirely distinct from already known modes of action, therefore demonstrating the potential for development of novel anti-bacterial agents.     

植物多肽抗生素研究进展

植物多肽抗生素是一类对细菌、真菌等微生物及某些昆虫和动植物细胞具有抑制或杀灭作用的小分子多肽. 根据多肽抗生素的氨基酸序列及二级结构,可将植物多肽抗生素分为9类,包括硫素（thionins）、植物防御素（plant defensins）、转脂蛋白（lipid transfer proteins, LTPs）、橡胶素（heveins）、打结素（knottins）、凤仙花素(1b-AMPs)和新近发现的荠菜素（shepherdins）、蜕皮素（snakins）、环肽（cyclotides）. 对近年来植物多肽抗生素的分类、抗菌机理、生物活性及基因工程等方面的研究情况作一介绍,希望有助于我国在这一领域的研究与开发.     

Biophysical and medical and biological aspects of use of polyene antibiotics in combination with dimethylsulfoxide

Modern conceptions of the physicochemical properties of dimethylsulfoxide and polyene antibiotics are reviewed. The results of investigations of independent and mutual effects of polyene antibiotics and dimethylsulfoxide on membrane permeability were analysed. The own experimental data of radioprotective and antitumour action of complex dimethylsulfoxide-polyene antibiotics are presented, and the perspectives of their use in medicine are described.     

Inhibition of the resuscitation from the viable but non-culturable state in Enterococcus faecalis

The viable but non-culturable (VBNC) state is a survival strategy adopted by bacteria when exposed to environmental stresses capable of inducing cell growth inhibition and cell death. This state can be summarized as a quiescent form of life waiting for suitable conditions. This strategy has been shown to be activated by medically important bacteria either when present in natural environments or in the human body during the infection process. In this study we have evaluated the effects of antibiotics acting on peptidoglycan or protein synthesis of Enterococcus faecalis in the VBNC state. The activity of the antibiotics was determined by their ability both to inhibit resuscitation (i.e. recovery of cell division) and to bind the molecular target of action. Benzylpenicillin, piperacillin and gentamicin block cell resuscitation at the minimal inhibitory concentrations (MICs) of growing cells, while vancomycin acts only at doses 500 times higher than the MIC. This different behaviour is discussed taking into consideration the mode of action of the antibiotics.     

The immunomodulating action of aminoglycoside antibiotics via different administration technics]

It was shown that intramuscular administration of aminoglycosides such as gentamicin and amikacin had an immunosuppressive action in healthy animals. Administration of the antibiotics entrapped in erythrocyte shades increased the immune response. The immunostimulating effect was higher when the aminoglycosides entrapped in allogenic erythrocytes were administered. After the routine administration of the antibiotics they were detected in the blood and urine within the first hours after the administration. After administration of the antibiotics entrapped in erythrocyte shades their detection was later in time. When the aminoglycosides entrapped in allogenic erythrocytes were administered they were not detected in the biological fluids.     

Study of embryotoxic and teratogenic effects of amphotericin B and a methyl derivative of amphotericin B in rats after their intravenous and intra-amniotic administration]

The embryotoxic action of amphotericin B and its methyl derivative was compared in rats after their intravenous and intraamniotic administration. The concentrations of amphotericin B and its methyl derivative in the amniotic cavity on days 13, 14 and 15 of pregnancy were 1.5 and 36 micrograms/ml, respectively. When administered intravenously during the preimplantation period the antibiotics had no embryotoxic action. Intravenous administration of amphotericin B in a dose of 500 micrograms/kg and its derivative in a dose of 2000 micrograms/kg during organ genesis induced a decrease in the craniocaudal size. In a dose of 3000 micrograms/kg administered intravenously the methyl derivative of amphotericin B induced an increase in postimplantation death rates. Administration of amphotericin B to the amniotic cavity had no damaging action. Administration of the methyl derivative on day 15 of pregnancy led to anomalous development of the lower extremities and slower ossification. The threshold doses by the embryotoxic action for intravenous administration are 500 micrograms/kg for amphotericin B and 2000 micrograms/kg for the methyl derivative. Administration of the antibiotics to the amniotic cavity revealed potential teratogenic properties of the amphotericin B methyl derivative.     

Antibacterial plant compounds,extracts and essential oils: An updated review on their effects and putative mechanisms of action

Background: Antibiotic-resistant bacteria pose a global health threat. Traditional antibiotics can lose their effectiveness, and the development of novel effective antimicrobials has become a priority in recent years. In this area, plants represent an invaluable source of antimicrobial compounds with vast therapeutic potential.Purpose: To review the full possible spectrum of plant antimicrobial agents (plant compounds, extracts and essential oils) discovered from 2016 to 2021 and their potential to decrease bacterial resistance. Their activities against bacteria, with special emphasis on multidrug resistant bacteria, mechanisms of action, possible combinations with traditional antibiotics, roles in current medicine and future perspectives are discussed.Methods: Studies focusing on the antimicrobial activity of compounds of plant origin and their mechanism of action against bacteria were identified and summarized, including contributions from January 2016 until January 2021. Articles were extracted from the Medline database using PubMed search engine with relevant keywords and operators.Results: The search yielded 11,689 articles from 149 countries, of which 101 articles were included in this review. Reports from 41 phytochemicals belonging to 20 families were included. Reports from plant extracts and essential oils from 39 plant species belonging to 17 families were also included. Polyphenols and terpenes were the most active phytochemicals studied, either alone or as a part of plant extracts or essential oils. Plasma membrane disruption was the most common mechanism of antimicrobial action. Number and position of phenolic hydroxyl groups, double bonds, delocalized electrons and conjugation with sugars in the case of flavonoids seemed to be crucial for antimicrobial capacity. Combinations of phytochemicals with beta-lactam antibiotics were the most studied, and the inhibition of efflux pumps was the most common synergistic mechanism.Conclusion: In recent years, terpenes, flavones, flavonols and some alkaloids and phenylpropanoids, either isolated or as a part of extracts, have shown promising antimicrobial activity, being membrane disruption their most common mechanism. However, their utilization as appropriate antimicrobials need to be boosted by means of new omics technologies and network pharmacology to find the most effective combinations among them or in combination with antibiotics.     

Silver potentiates aminoglycoside toxicity by enhancing their uptake

The predicted shortage in new antibiotics has prompted research for chemicals that could act as adjuvant and enhance efficacy of available antibiotics. In this study, we tested the effects of combining metals with aminoglycosides on Escherichia coli survival. The best synergizing combination resulted from mixing aminoglycosides with silver. Using genetic and aminoglycoside uptake assays, we showed that silver potentiates aminoglycoside action in by‐passing the PMF‐dependent step, but depended upon protein translation. We showed that oxidative stress or Fe–S cluster destabilization were not mandatory factors for silver potentiating action. Last, we showed that silver allows aminoglycosides to kill an E. coli gentamicin resistant mutant as well as the highly recalcitrant anaerobic pathogen Clostridium difficile. Overall this study delineates the molecular basis of silver's potentiating action on aminoglycoside toxicity and shows that use of metals might offer solutions for battling against increased bacterial resistance to antibiotics.     

Target cell specificity of a bacteriocin molecule: a C-terminal signal directs lysostaphin to the cell wall of Staphylococcus aureus.

Microbial organisms secrete antibiotics that cause the selective destruction of specific target cells. Although the mode of action is known for many antibiotics, the mechanisms by which these molecules are directed specifically to their target cells hitherto have not been described. Staphylococcus simulans secretes lysostaphin, a bacteriolytic enzyme that cleaves staphylococcal peptidoglycans in general but that is directed specifically to Staphylococcus aureus target cells. The sequence element sufficient for the binding of the bacteriocin as well as of hybrid indicator proteins to the cell wall of S.aureus consisted of 92 C-terminal lysostaphin residues. Targeting to the cell wall of S.aureus occurred either when the hybrid indicator molecules were added externally to the bacteria or when they were synthesized and exported from their cytoplasm by an N-terminal leader peptide. A lysostaphin molecule lacking the C-terminal targeting signal was enzymatically active but had lost its ability to distinguish between S.aureus and S.simulans cells, indicating that this domain functions to confer target cell specificity to the bacteriolytic molecule.     

Biologically active nonribosomal peptides. I. Nonribosamal polypeptide antibiotics

The data on novel polypeptide antibiotics described within the last 10-15 years, as well as new researches on the known antibiotics with respect to their mechanisms of action and microbial resistance are presented.