Sensitivity of bifidobacteria to antibacterial drugs

Twenty one strains of bifidobacteria belonging to various species were studied with respect to their sensitivity to antibacterial drugs most widely used in medical practice. The strains were isolated from practically healthy persons and from persons in contact with antibiotics in their production. It was found that sensitivity of the strains was the highest with respect to penicillins and tetracyclines. With respect to kanamycin, monomycin and levomycetin the strains were resistant. Strain differences in resistance to separate antibacterial drugs were observed. Increased streptomycin and tetracycline resistance of the strains isolated from the persons being for a prolonged period in contact with these antibiotics in their production, was stated.     

Sensitivity of Pseudomonas to currently used antibacterial drugs

Sensitivity of 184 strains of four Preudomonas species that are of importance from the medical viewpoint was studied. It was shown that all the studied strains were resistant to cefazolin and ampicillin. Sulfomonomethoxine was active only against P. mallei. Gentamicin inhibited the growth of all the strains of P. mallei and 60 per cent of the strains of P. aeruginosa. Among the four studied strains, the causative agent of glanders was the least resistant to the chemotherapeutic drugs. Eleven out of the 16 studied drugs were active against P. mallei. The strains of P. pseudomallei, the organism causing melioidosis were sensitive to 6 drugs: ceftazidime, imipenem, doxycycline, minocycline, chloramphenicol and biseptol. The dime, ceftriaxone, cefsulodin, cefoperazone, cefotaxime, piperacillin and imipenem. The strains of P. cepacia were the most resistant to all the chemotherapeutic drugs studied and only biseptol was active in the concentrations attained in blood of patients (MIC50 12.5 mg/l). 10 to 70 per cent of the strains were sensitive to ceftazidime, imipenem, doxycycline, minocycline and rifampicin. Therefore, imipenem and ceftazidime were the most active drugs with respect to the causative agents of pseudomonoses. Biseptol, doxycycline and minocycline are also worthy note.     

Late stage antibacterial drugs in the clinical pipeline

Bacterial resistance to antimicrobial agents is a growing problem worldwide. Not only is issue compounded by the fact that there are fewer pharmaceutical companies conducting research to discover novel antimicrobials than in the past but development time lines have stretched so that a dozen years from discovery to the market is now the standard. Eleven antibacterial drugs in late stage clinical development are discussed. Whereas many of these may successfully deal with resistant strains of Gram-positive pathogens, there is very little in development to address the gorwing unmet medical need of multi-drug resistant Gram-negative infections.     

Combination drugs, an emerging option for antibacterial therapy

The emerging and sustained resistance to antibiotics and the poor pipeline of new antibacterials is creating a major health issue worldwide. Bacterial pathogens are increasingly becoming resistant even to the most recently approved antibiotics. Few antibiotics are being approved by regulatory organizations, which reflects both the difficulty of developing such agents and the fact that antibiotic discovery programs have been terminated at several major pharmaceutical companies in the past decade. As a result, the output of the drug pipelines is simply not well positioned to control the growing army of resistant pathogens, although academic institutions and smaller companies are trying to fill that gap. An emerging option to fight such pathogens is combination therapy. Combinations of two antibiotics or antibiotics with adjuvants are emerging as a promising therapeutic approach. This article provides and discusses clinical and scientific challenges to support the development of combination therapy to treat bacterial infections.     

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.     

Comparative genomic assessment of novel broad-spectrum targets for antibacterial drugs

Single and multiple resistance to antibacterial drugs currently in use is spreading, since they act against only a very small number of molecular targets; finding novel targets for anti-infectives is therefore of great importance. All protein sequences from three pathogens (Staphylococcus aureus, Mycobacterium tuberculosis and Escherichia coli O157:H7 EDL993) were assessed via comparative genomics methods for their suitability as antibacterial targets according to a number of criteria, including the essentiality of the protein, its level of sequence conservation, and its distribution in pathogens, bacteria and eukaryotes (especially humans). Each protein was scored and ranked based on weighted variants of these criteria in order to prioritize proteins as potential novel broad-spectrum targets for antibacterial drugs. A number of proteins proved to score highly in all three species and were robust to variations in the scoring system used. Sensitivity analysis indicated the quantitative contribution of each metric to the overall score. After further analysis of these targets, tRNA methyltransferase (trmD) and translation initiation factor IF-1 (infA) emerged as potential and novel antimicrobial targets very worthy of further investigation. The scoring strategy used might be of value in other areas of post-genomic drug discovery.     

Competition of antibacterial drugs for binding sites of human serum albumin

Simultaneous binding of two drugs to human serum albumin (HSA) was studied by flow microcalorimetry. The following drug pairs were used: sulfadimethoxine and cefazolin. Sulfadimethoxine and dicloxacillin, sulfadimethoxine and chlortetracycline. A procedure for estimating the calorimetric titration curves in competing binding of the drugs to the HSA homogeneous active site is described. Comparison of the theoretical and experimental titration curves enabled detection of the ligand competition for the biopolymer binding site. It was shown that sulfadimethoxine displaced cefazolin in the HSA active site, the nature of the HSA association with dicloxacillin and sulfadimethoxine was independent and binding of doxycycline or chlortetracycline to HSA had no influence on sulfadimethoxine interaction with protein.     

Rapid evaluation of the effectiveness of antibacterial drugs in experimental tularemia

Rapid estimation of the protective effect of antibacterial drugs on Fransiella tularensis for not more than 2 days was shown possible in experiments on albino mice infected with tularemia. High efficacy of aminoglycosides (kanamycin, gentamicin, streptomycin, amikacin, netilmicin, tobramycin, sagamycin, ribostamycin and sisomicin), tetracyclines (tetracycline, doxycycline, minocycline and methacycline), rifampicin, phosphomycin and oxolinic acid was determined with the recommended rapid method. Amoxycillin, ampicillin, piperacillin, carbenicillin, erythromycin, levomycetin, cefradine, cefmetazole, cefatrizine, cefoxitin, cefsulodin and bactrim (biseptol) proved to be inefficient against the tularemia causative agent.     

Novel 4-thiazolidinone derivatives as potential antifungal and antibacterial drugs

As part of ongoing studies in developing new antimicrobials, a class of structurally novel 4-thiazolidinone derivatives incorporating three known bioactive nuclei such as thiazole, thiazolidinone and adamantane was synthesized by the multi-step reaction protocol, already reported in the literature. NMR and Molecular Modeling techniques were employed for structure elucidation and Z/E potential isomerism configuration of the analogues. Evaluation of antibacterial and antifungal activity showed that almost all compounds exhibited better results than reference drugs thus they could be promising candidates for novel drugs.     

Sensitivity of Corynebacterium diphtheriae isolated in Saint-Petersburg to antibacterial drugs]

One hundred and thirty strains of Corynebacterium diphtheriae isolated in St. Petersburg (42 toxigenic and 88 nontoxigenic) were tested with the method of serial dilutions in solid media for their susceptibility to 20 antibacterial drugs. The MICs of the drugs for the isolates ranged from < or = 0.015 to > or = 32.0 micrograms/ml. 13 per cent of the isolates was resistant at least to one antibacterial drug. The isolates resistant to erythromycin (11.5 per cent), lincomycin (11.5 per cent) and trimethoprim (8.5 per cent) were most frequent. 3 isolates (2.3 per cent) had multiple resistance to 8 drugs: benzylpenicillin, ampicillin, oxacillin, chloramphenicol, erythromycin, lincomycin, trimethoprim, and nitroxolin. No significant differences in the susceptibility of the toxigenic and nontoxigenic strains of C. diphtheriae were detected. Gentamicin, rifampicin, tetracycline, doxycycline and pefloxacin were the most active antibiotics.     

Synthesis of novel selenium containing sulfa drugs and their antibacterial activities

Synthesis of 3-[4-(N-substituted sulfamoyl)phenyl]-3,4-dihydro-4-oxo-7,9-dimethylpyri-do[3′,2′:4,5]selenolo[3,2-d]pyrimidines,7-[4-(N-substituted sulfamoyl)phenyl]-7,8-dihydro-8-oxo-3,4-diphenylpyrimido[4′,5′:4,5]selenolo [2,3-c]pyridazines and 1-[4-(N-substituted sulfamoyl)phenyl]-1,11-dihydro 11-oxo-4-methylpyrimido[4′,5′:4,5]selenolo[2,3-b]quinolines is reported. 4-Amino-N-pyrimidine-2-ylbenzene sulfonamide (a), 4-amino-N-(2,6-dimethylpyrimidin-4-yl)benzene sulfonamide (b), N-[(4-aminophenyl)sulfonyl] acetamide (c) with N-ethoxymethyleneamino of selenolo pyridine, selenolo pyridazine and selenolo quinoline derivatives respectively were obtained starting from 1-amino-N ⁴-substituted sulfanilamides. Spectroscopic data (IR, ¹H NMR, ¹³C NMR and Mass spectral) confirmed the structure of the newly synthesized compounds. Substituted pyrimidines, pyridazines and quinolines were screened for antibacterial activity against gram-positive and gram-negative bacteria. Selenolo derivative of N-[(4-aminophenyl)sulfonyl] acetamide (substitutent of sulfacetamide c) showed strong bactericidal effect against all the tested organisms. Selenolo[3,2-d]pyrimidin (substitutent a) showed a good bactericidal effect against Serratia marcescens, Staphylococcus aureus and Escherichia coli. Compounds selenolo[2,3-c]pyridazine (substitutent b), selenolo[2,3-b]quinoline(substitutents c)) exhibited a moderate bactericidal effect against Serratia marcescens. None of the synthesized seleno pyridazines has a considerable antimicrobial activity against the tested organisms. The minimum inhibitory concentration (MIC) of the most active compound-3-[4-(N-acetyl sulfamoyl)phenyl]-3,4-dihydro-4-oxo-7,9-dimethylpyrido[3′,2′:4,5]selenolo [3,2-d]pyrimidine was 10 mg ml⁻¹.