Preparation and in vitro anti-staphylococcal activity of novel 11-deoxy-11-hydroxyiminorifamycins

We report herein the preparation and anti-staphylococcal activity of a series of novel 11-deoxy-11-hydroxyiminorifamycins. Many of the compounds synthesized exhibit potent activity against wild-type Staphylococcus aureus with MICs equivalent to, or better than, rifamycin reference agents. In addition, some of the compounds retain potent activity against an intermediate rifamycin-resistant strain of Staphylococcus aureus. For instance, compound 5k exhibits an MIC of 0.12 microg/mL against an intermediate rifamycin-resistant strain, while the rifamycin reference agents, rifampin and rifalazil, exhibit MICs of 16 microg/mL and 2 microg/mL, respectively, against the same strain.     

Structure-guided design,synthesis and biological evaluation of novel DNA ligase inhibitors with in vitro and in vivo anti-staphylococcal activity

A series of 2-amino-[1,8]-naphthyridine-3-carboxamides (ANCs) with potent inhibition of bacterial NAD⁺-dependent DNA ligases (LigAs) evolved from a 2,4-diaminopteridine derivative discovered by HTS. The design was guided by several highly resolved X-ray structures of our inhibitors in complex with either Streptococcus pneumoniae or Escherichia coli LigA. The structure–activity-relationship based on the ANC scaffold is discussed. The in-depth characterization of 2-amino-6-bromo-7-(trifluoromethyl)-[1,8]-naphthyridine-3-carboxamide, which displayed promising in vitro (MIC Staphylococcus aureus 1 mg/L) and in vivo anti-staphylococcal activity, is presented.     

The anti-staphylococcal activity of Angelica dahurica (Bai Zhi)

Bioassay-guided fractionation of a hexane extract prepared from the roots of the Chinese drug Angelica dahurica (Bai Zhi) led to the isolation of the polyacetylenic natural product falcarindiol (1). The absolute stereochemistry of this compound was confirmed by careful 1H NMR analysis of its (R)- and (S)-Mosher ester derivatives as the 3(R), 8(S) isomer. Activity was tracked using a Mycobacterium fortuitum screening assay and the purified product was evaluated against multidrug-resistant and methicillin-resistant strains of Staphylococcus aureus (MRSA). The minimum inhibitory concentrations (MIC) of this metabolite ranged from 8 to 32 microg/ml highlighting the potential of the acetylene natural product class as antibiotic-lead compounds. These MIC values compare favourably with some of the newest agents in development for the treatment of MRSA infection and indicate that further evaluation of the antibiotic activity of acetylenes is warranted.     

Donor activity of methicillin resistant staphylococci in transduction experiments]

Antibiotic resistance gene transmission from methicillin resistant strains of Staphylococcus aureus (MRSA), isolated in a burn care unit, was studied in transduction experiments with type phages 29, 52, 52A and in experiments with prophage induction. The results of the experiments demonstrated high donor activity of MRSA. Recombinants with different antibiotic resistance phenotypes were revealed, but there were no methicillin resistant staphylococci among them. Stability of cloramphenicol resistance gene transmission in the experiments on specific transduction with the prophage induction could be indicative of the prophage localization near the chloramphenicol resistance genes. Variety of the antibiotic resistance combinations in the transductants from the clinical strains of MRSA could prove heterogeneity of the strains even under conditions of one hospital.     

Occurrence of Staphylococcus aureus and evaluation of anti-staphylococcal activity of Lactococcus lactis subsp. lactis in ready-to-eat poultry meat

A total of 181 ready-to-eat poultry meat samples were examined for the presence of Staphylococcus aureus, and 11 (6 %) were found to have S. aureus contamination. Of 11 S. aureus isolates, 10 (91 %) were resistant to at least one antibiotic used in this study, and 2 were resistant to oxacillin. Lactococcus lactis subsp. lactis was tested as a bio-control agent. All the S. aureus isolates were found to be sensitive to antimicrobial products in L. lactis subsp. lactis supernatants; the zones of inhibition were in the range of 5.0 mm?±?0.70 mm to 19.8 mm?±?0.83 mm with the majority of isolates. As a competitive flora in mixed culture (LAPTg broth) and protective culture in poultry meat, L. lactis subsp. lactis was effective against S. aureus isolates; the growth of S. aureus isolates was almost negative after 32 h incubation in mixed culture. The population of S. aureus was reduced substantially to almost log 1 CFU/g after 25 days of incubation in protective culture. The pH of the test cultures also decreased sharply with time.     

The combined effect of methicillin and teicoplanin against Staphylococcus aureus strains investigated in vitro

The synergy or antagonism between teicoplanin and methicillin against the methicillin-resistant strains of Staphylococcus aureus with decreased susceptibility to vancomycin was studied using agar dilution and E-tests. The investigated strains were GISA and h-GISA isolated in our laboratory as well as standard. In the used range of concentrations, a synergy was shown in the case of two strains and an antagonism was shown in the case of other two strains. For the most strains the tested combination of antibiotics showed indifference. The antagonistic effect was observed in the case of the standard strain Mu3 and the one from eight strains h-GISA isolated in our laboratory.     

Detachment characteristics and oxacillin resistance of Staphyloccocus aureus biofilm emboli in an in vitro catheter infection model

Catheter-related bloodstream infections due to Staphylococcus aureus are of increasing clinical importance. The pathophysiological steps leading to colonization and infection, however, are still incompletely defined. We observed growth and detachment of S. aureus biofilms in an in vitro catheter-infection model by using time-lapse microscopy. Biofilm emboli were characterized by their size and their susceptibility for oxacillin. Biofilm dispersal was found to be a dynamic process in which clumps of a wide range of diameters detach. Large detached clumps were highly tolerant to oxacillin compared with exponential-phase planktonic cultures. Interestingly, the degree of antibiotic tolerance in stationary-phase planktonic cultures was equal to that in the large clumps. The mechanical disruption of large clumps reduced the minimal bactericidal concentration (MBC) by more than 1,000 times. The MBC for whole biofilm effluent, consisting of particles with an average number of 20 bacteria was 3.5 times higher than the MBC for planktonic cultures. We conclude that the antibiotic resistance of detached biofilm particles depends on the embolus size and could be attributed to nutrient-limited stationary-phase physiology of cells within the clumps. We hypothesize that the detachment of multicellular clumps may explain the high rate of symptomatic metastatic infections seen with S. aureus.     

Synthesis and anti-staphylococcal activity of novel bacterial topoisomerase inhibitors with a 5-amino-1,3-dioxane linker moiety

Novel bacterial type II topoisomerase inhibitors (NBTIs) constitute a promising new class of antibacterial agents. We report a series of NBTIs with potent anti-staphylococcal activity and diminished hERG inhibition. Dioxane-linked compound 9 demonstrated MICs ≤1?μg/mL against both methicillin-susceptible (MSSA) and -resistant Staphylococcus aureus (MRSA), accompanied by reduced hERG inhibition as compared to cyclohexane- or piperidine-linked analogs.     

Potentiation of methicillin activity against methicillin-resistant Staphylococcus aureus by diterpenes

Totarol is a diterpene compound extracted from the totara tree. Totarol and eight other diterpenes were found to potentiate methicillin, one reducing the minimum inhibitory concentration of methicillin against resistant Staphylococcus aureus 256-fold. Totarol did not inhibit the synthesis of DNA or peptidoglycan in S. aureus, but reduced the respiration rate by 70%. Under potentiation conditions, diterpenes had only a slight effect on the respiration rate, but had a significant effect on expression of PBP 2a. We conclude that the primary staphylococcal target for totarol is the respiratory chain, but that potentiation of methicillin by diterpenes is by interference with PBP 2a expression.     

Study of the therapeutic effectiveness of oxacillin in treating the infectious forms of syphilis]

Data on efficiency of oxacillin therapy as applied to 45 patients with contagious forms of syphilis are presented. The drug was administered orally and intramuscularly to 40 and 5 patients respectively for 20 days. The periods of clearance from Trepanoma pallidum, disappearance of the external syphilis manifestations and the rate of the decrease in the titer of the serological reaction reagins are presented. The levels of oxacillin in the blood serum of 24 patients were determined for 5--6 hours from the moment of the treatment beginning. The study showed therapeutic efficiency of oxacillin.