ABSTRACT
italic>Mycobacterium tuberculosis, responsible for tuberculosis (TB), remains a major health problem worldwide and is one of the infectious diseases causing increased morbidity and mortality worldwide. Biotin, namely vitamin H, is an important cofactor necessary for fatty acid biosynthesis, gluconeogenesis and amino acid metabolism in organisms including Mycobacterium tuberculosis. Due to its inability to ingestion biotin from outside, Mycobacterium tuberculosis can only obtain biotin through biotin biosynthesis. Different from the classical BioC-BioH, BioI-BioW and non-classical BioZ pathways, Mycobacterium tuberculosis synthesized biotin by "BioC-BioH(2)" pathway in the early stage. This review focuses on the unique biotin synthesis pathway of Mycobacterium tuberculosis and its key genes, especially the response of this pathway and biotin-dependent carboxylase to tuberculosis first-and second-line drugs, as well as inhibitors and natural products targeting biotin synthesis.
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Based on the idea of multi-target drug design, taking p-aminosalicylic acid (PAS) as the parent nucleus, the unreported target molecules TM1 and TM2 were designed with PAS, isonicotinic acid and fluoroquinolone as three structural units conjugated by different linkers. Sixteen target molecules were synthesized by multi-step reaction, and their activities against Mycobacterium tuberculosis and human pathogenic bacteria were evaluated. The results showed that the anti-tuberculosis activity of TM2a was stronger than those of the assayed fluoroquinolones, while TM1a was comparable to that of clinafloxacin, the most active compound of the positive control fluoroquinolones; TM1a showed the strongest inhibitory activity to all almost tested strains, TM1b and TM2a showed very strong inhibitory activity to most strains, and TM1h/2h had strong inhibitory activity to some strains; The inhibitory activities of TM1a/1h on Staphylococcus aureus ATCC14125 are much stronger than those of fluoroquinolones, which eminently deserves further study. The hemolysis test results showed that the highly active molecules TM1a and TM2a exhibited relative safety below the concentrations of 8 and 32 μg·mL-1, respectively. In this study, a new hybrid molecule of three molecular pharmacophores with PAS as the parent nucleus was synthesized for the first time, and some of which have highly strong antibacterial activity, which provides a new idea for the research and development of antibiotics.
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Tuberculosis (TB) caused by Mycobacterium tuberculosis (M. tuberculosis) infection remains a major public health problem of global concern, largely due to antibiotics resistance, persistence and immune evasion. Sphingolipid bioactive molecules are involved in several important pathophysiological processes. Sphingosine-1-phosphate is a key product of sphingolipid metabolism, and can play a role in two manners: autocrine and/or paracrine. Sphingosine-1-phosphate regulates T cells and a variety of antigen-presenting cells during M. tuberculosis infection, promotes antigen processing and expression in monocytes, is involved in the maturation of phagolysosome, regulates Ca2+ homeostasis, participates in the autophagy of macrophages, inhibits the survival and proliferation of M. tuberculosis within host cells, and effectively reduces the necrosis of the mouse lungs infected by M. tuberculosis. Injection of 20 nmol per mouse sphingosine-1-phosphate inhibited up to 47% of mycobacterial growth in the lung and spleen of mice infected by M. tuberculosis. In this paper, sphingosine-1-phosphate, its receptors and regulatory network were reviewed, and the specific mechanism of sphingosine-1-phosphate inhibiting the survival of M. tuberculosis-infected host cells was elaborated. This will provide novel insights into the new targets for tuberculosis prevention and treatment.
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Cryptococcal meningitis, caused by fungus Cryptococcus neoformans, is responsible for over a million infections and 600 000 deaths annually. Largely due to the limited treatment options and the intrinsic drawbacks coupled with drug resistance to current therapies, it is urgent to discover novel antifungal agents against cryptococcosis. An ideal antifungal drug should at least satisfy the following criteria: fungicidal, fungus-specific, permeable for the host barriers such as cell membranes of phagocytes and the blood-CNS barrier. Both discovery of candidates with novel mode of action and repurposing existing molecules with potent anti-cryptococcal activity are effective ways in discovery of new anti-cryptococcal agents. Here, we summarized recent advances in the study of anti-fungal activities, mechanisms of action, and clinical developments of new anti-cryptococcal drugs.
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Bacterial communities usually develop biofilms abound in nature niche. The development of biofilm is a highly dynamic and complex process coordinated by multiple mechanisms, of which two-component system and quorum sensing are two well-defined systems. Biofilm is involved in the virulence of many pathogens. Therefore, targeting the key factors involved in the biofilm formation represents a novel and promising avenue for developing better antibiotics.
Subject(s)
Acyl-Butyrolactones , Metabolism , Bacteria , Genetics , Metabolism , Bacterial Proteins , Genetics , Metabolism , Biofilms , Drug Delivery Systems , Gene Expression Regulation, Bacterial , Homoserine , Metabolism , Lactones , Metabolism , Quorum Sensing , Signal TransductionABSTRACT
Nanomedicine offers great promise for early diagnosis and treatment of formidable diseases. The unique morphology and biology characteristics of bacteriophage provide unprecedented opportunity for such endeavor. The paper summarizes the application of bacteriophage in nanobiomaterials, nanomedicine, nanomedicine delivery and nanodiagnosis, especially the nano-imaging reagents and future direction concerning nanomedicine based on bacteriophage.
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Humans , Bacteriophages , Diagnostic Imaging , Drug Delivery Systems , Early Diagnosis , Nanomedicine , NanotechnologyABSTRACT
New antibiotics with novel modes of action and structures are urgently needed to combat the emergence of multidrug-resistant bacteria. Bacterial signal peptidase I (SPase I) is an indispensable enzyme responsible for cleaving the signal peptide of preprotein to release the matured proteins. Increasing evidence suggests that SPase I plays a crucial role in bacterial pathogenesis by regulating the excretion of a variety of virulent factors, maturation of quorum sensing factor and the intrinsic resistance against beta-lactams. Recently, breakthrough has been achieved in the understanding of three-dimensional structure of SPase I as well as the mechanism of enzyme-inhibitors interaction. Three families of inhibitors are identified, i.e. signal peptide derivatives, beta-lactams and arylomycins. In this article, we summarize the recent advance in the study of structure, activity and structure-activity relationship of SPase I inhibitors.
Subject(s)
Animals , Anti-Bacterial Agents , Pharmacology , Bacteria , Escherichia coli , Membrane Proteins , Metabolism , Oligopeptides , Chemistry , Pharmacology , Serine Endopeptidases , Metabolism , Serine Proteinase Inhibitors , Chemistry , Pharmacology , Structure-Activity Relationship , beta-LactamsABSTRACT
The fluoroquinolones are the most widely used broad-spectrum antibiotics, accounting for 18% of global antibacterial market share. They can kill bacteria rapidly with variety of derivatives available. Different quinolones vary significantly in rate and spectrum of killing, oxygen requirement for metabolism and reliance upon protein synthesis. Further understanding the sophisticated mechanisms of action of this important antibiotic family based on the molecular genetic response of bacteria can facilitate the discovery of better quinolone derivatives. Factors such as SOS response, bacterial toxin-antitoxin system, programmed death, chromosome fragmentation and reactive oxygen have been implicated in the action to some extent. "Two steps characteristic" of quinolones killing is also emphasized, which might inspire future better quinolones modification.
Subject(s)
Anti-Bacterial Agents , Pharmacology , Apoptosis , Bacteria , Genetics , Chromosomes, Bacterial , DNA Cleavage , DNA Gyrase , DNA Replication , DNA Topoisomerases , Fluoroquinolones , Pharmacology , Quinolones , Pharmacology , Reactive Oxygen Species , SOS Response, GeneticsABSTRACT
<p><b>OBJECTIVE</b>To compare the sensitivities of MALDI-TOF MS and direct PCR sequencing on gene mutations detection of hepatitis B virus.</p><p><b>METHODS</b>100 serum samples from chronic hepatitis B patients were collected, which consisted of 90 serum samples (study group) from 90 chronic hepatitis B patients received nucleoside analogues (NA) therapy for more than 1 year and HBV DNA titer still higher than 500 copies/ml and 10 serum samples (blank group) from 10 chronic hepatitis B patients never treated with antiviral therapy and HBV-DNA titer higher than 1 x 10(5) copies/ml. 9 known mutations associated with HBV P gene in these samples were detected by MALDI-TOF MS and direct PCR sequencing at the same time, TYPE4.0 software and Sequence Navigator software were used to analyze the results separately.</p><p><b>RESULTS</b>(1) In study group, mutations were detected in 53 samples and the total mutation sites were 86 by MALDI-TOF MS with a positive detection rate of 58.89%, whereas only 19 samples were found with mutations and totally 28 mutation sites were detected by direct PCR sequencing, the positive detection rate was 21.11%. The positive detection rate by MALDI-TOF MS was higher than that by direct PCR sequencing and the difference was statistically significant (P < 0.05). In blank group, no mutations were detected by any method. (2) In study group, when the HBV DNA titers were at 500-1000 copies/ml, 10(3)-10(4) copies/ml and 10(4)-10(5) copies/ml, the positive mutation detection rates by MALDI-TOF MS were 50%, 52.08% and 77.27% respectively, higher than that by direct PCR sequencing, which were only 0%, 8.33% and 45.45%. The difference was still statistically significant (P < 0.05).</p><p><b>CONCLUSIONS</b>MALDI-TOF MS had higher detection sensitivity for known mutation sites as compared to direct PCR sequencing method.</p>
Subject(s)
Humans , DNA Mutational Analysis , Drug Resistance, Viral , Genetics , Hepatitis B virus , Genetics , Mutation Rate , Polymerase Chain Reaction , Sensitivity and Specificity , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , MethodsABSTRACT
Reversible protein phosphorylation regulates multiple biochemical events. Mycobacterium tuberculosis phosphatases play important roles in regulating the pathogen physiology and interference of host signaling. They are also involved in the evasion of host immune response and blockage of the phagosome-lysosome fusion. Selective inhibition of phosphatase represents an ideal new avenue of anti-tuberculosis drug design. In this paper, we update the progresses about the regulation network of Mycobacterium tuberculosis phosphatases including MptpA, MptpB, MstP, SapM and their inhibitors. These serve as the basis for further antituberculosis drug target.
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Animals , Humans , Acid Phosphatase , Metabolism , Antitubercular Agents , Pharmacology , Bacterial Proteins , Metabolism , Mycobacterium tuberculosis , Protein Tyrosine Phosphatases , MetabolismABSTRACT
Last two decades have witnessed the resurging of tuberculosis (TB) and multi-drug resistant TB, even the extensive drug resistant TB. It is urgent to develop novel drug to combat the increasingly worsen TB. Capreomycin is an ideal second-line TB drug. It is also recognized as an attractive template to develop more peptide antibiotics. In this review, the biosynthesis gene cluster of capreomycin, the action mechanism unveiled by transcriptome and novel resistance rational are summarized from the recent functional genomic investigation.
Subject(s)
Antibiotics, Antitubercular , Chemistry , Pharmacology , Capreomycin , Chemistry , Pharmacology , Drug Resistance, Multiple, Bacterial , Genes, Bacterial , Mycobacterium tuberculosis , Genetics , Open Reading Frames , Ribosomal Proteins , Metabolism , Tuberculosis, Multidrug-Resistant , Drug TherapyABSTRACT
Drug resistant bacteria is an increasingly urgent challenge to public health. Bacteria adaptation and extensive abuse of antibiotics contribute to this dilemma. Active efflux of antibiotics is employed by the bacteria to survive the antibiotic pressure. Efflux pump is one of the hot spots of current drug related studies and ideal targets for the improvement of treatment. The efflux pumps and related mechanisms of action, regulation of expression and methodologies were summarized. Comparative genomics analyses were employed to elucidate the underlying mechanisms of action and evolution of efflux pump as exemplified by the Mycobacterium in our lab, which is a crucial re-emerging threat to global public health. The pathway and state-of-art drug development of efflux pump related drugs are included too.
Subject(s)
ATP-Binding Cassette Transporters , Physiology , Anti-Bacterial Agents , Metabolism , Pharmacology , Bacteria , Metabolism , Drug Resistance, Multiple, Bacterial , Genetics , Ion Pumps , Physiology , Membrane Transport Proteins , Physiology , Multidrug Resistance-Associated Proteins , Physiology , Mycobacterium , MetabolismABSTRACT
There are similarities between magnetotactic bacteria and Acidithiobacillus ferrooxidans (A. ferrooxidans) which isolated from Acid mine drainage(AMD). The weak magnetotaxis of some bioleaching bacteria isolated were found by microscope. A magnetophoresis apparatus was designed based on these weak magnetotaxis and be used to analysis the movement of these strains. The physiological properties of the anear magnetic field strain and removed magnetic field strain which isolated successfully by magnetophoresis apparatus have large difference. The nanometer magnetic particles was extract from the Acidithiobacillus ferrooxidans which purified by spread plate method from AMFS and its main elements are Fe and O by energy spectrum analysis. The results show that A. ferrooxidans have weak magnetotaxis and can be isolated by magnetophoresis. With the development of this new isolating method, the research of magnetotactic bacteria and bioleaching will get more benefit from it.
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OBJECTIVE@#To investigate the relationship between estrogen receptor (ER) gene polymorphisms and HBV-induced cirrhosis.@*METHODS@#Xba I and Pvu II polymorphisms of ER gene were analyzed in 98 patients with HBV-induced cirrhosis, 72 patients with chronic hepatitis B, and 84 healthy controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique.@*RESULTS@#The frequencies of Pp genotype and P allele of ER gene in patients with HBV-induced cirrhosis were higher than those in patients with chronic hepatitis B and controls, while the frequencies of pp genotype and p allele of ER gene in patients with HBV-induced cirrhosis were lower than those in patients with chronic hepatitis B and controls (P 0.05).@*CONCLUSION@#Pp genotype and P allele might be the susceptibility gene for HBV-induced cirrhosis while pp genotype and p allele might be the protective gene.
Subject(s)
Adolescent , Adult , Aged , Female , Humans , Male , Middle Aged , Alleles , Genotype , Hepatitis B, Chronic , Genetics , Liver Cirrhosis , Genetics , Polymerase Chain Reaction , Polymorphism, Genetic , Polymorphism, Restriction Fragment Length , Receptors, Estrogen , GeneticsABSTRACT
<p><b>OBJECTIVE</b>To identify enterovirus 71 (EV71) strains isolated from patients with hand, foot and mouth disease (HFMD) in Guangdong and Fujian provinces from 2000 to 2001 by using phylogenetic analysis.</p><p><b>METHODS</b>All 25 samples were first tested for enteric viruses by RT-PCR using enterovirus specific primers EV-1 and EV-2, and then were identified for EV71 by RT-PCR using EV71 specific primers 159S and 162A. The amplicons of 485bp segment (part of the VP1 gene) were cloned into pGEM-T and sequenced. A phylogenetic tree was constructed by comparison of the sequences with other 12 EV71 strains isolated from China, Japan, Hungary, and the United States including the prototype BrCr.</p><p><b>RESULTS</b>The positive rate of EV71 was about 20%. The sequence analysis showed that the new isolate (GZH2000) shared 94%-96% nucleotide identity with three strains isolated in 1998 and 2000, and 91% with a strain isolated in 1987 from Chinese mainland, but shared only 82%-84% homology with EV71 isolates studied abroad.</p><p><b>CONCLUSIONS</b>EV71 is one of the important pathogens of HFMD in south China. The strains isolated from mainland were closely related with most isolates from Taiwan, but different from most EV71 strains reported abroad. The symptoms of EV71 infection in mainland were not as intensive as those described in Taiwan's outbreak.</p>
Subject(s)
Adolescent , Child , Child, Preschool , Humans , Infant , China , Enterovirus , Genetics , Hand, Foot and Mouth Disease , Virology , Phylogeny , Sequence Analysis , Sequence Homology, Nucleic AcidABSTRACT
Expression microarray was employed in this study to investigate whether the ion channels and their regulatory elements encoding genes participate in the immune response to Mycobacterium tuberculosis infection. The results of a virulent strain were compared with those of the clinically isolated strains. The data demonstrate that K(+), Na(+), Ca(2+) and Cl(-) channels and their regulatory elements, such as the G protein, receptor and second messenger, protein kinase and protein phosphatase were involved in the immune reaction. The clinical strain affected more types of ion channels and respective regulatory elements. The data provides clues for further scrutiny into the role of ion channels and related elements in the interaction between Mycobacterium tuberculosis and host macrophage.
Subject(s)
Humans , Gene Expression Regulation , Ion Channels , Genetics , Macrophages , Allergy and Immunology , Microbiology , Mycobacterium tuberculosis , Virulence , Regulatory Elements, Transcriptional , Tuberculosis , Genetics , Allergy and Immunology , MicrobiologyABSTRACT
<p><b>OBJECTIVE</b>To understand the characteristics of human calicivirus (HuCV) infection in infants with diarrhea in Guangzhou city and to study genotype of the virus.</p><p><b>METHODS</b>The authors collected fecal specimens from 22 children with acute nonbacterial gastroenteritis from November to December, 2001. HuCV was detected from the specimens by RT-PCR. The PCR products were cloned into the PMD18-T cloning vector and sequenced.</p><p><b>RESULTS</b>HCV was detected from the specimens of 2 cases (9%, 2/22). The nucleotide sequence analysis revealed that the virus strains belonged to genotype 2 of Norwalk-like viruses.</p><p><b>CONCLUSION</b>HuCV is one of the pathogens causing diarrhea in infants and young children in Guangzhou area. HuCV infection occurred sporadically in autumn and winter.</p>