Two new 4'-acetylated analogs of chrysomycin were discovered during the screening for antitumor agents from the metabolites of actinomycetes. Their structures and physicochemical properties were determined by standard spectrometric analyses. Their cytotoxicities and antimicrobial activities were evaluated against a panel of cancer cell lines and microbes. While acetylation reinforced the cytotoxicity of chrysomycin B, it weakened the activity of chrysomycin A. Chrysomycin A and its acetylated analog showed high cytotoxicity toward most of the cancer cells with ICs less than 10 ng ml. The 4'-acetyl-chrysomycin A was predominantly observed in nuclei at concentrations where the autofluorescence was observable. Chrysomycins were effective toward Gram-positive bacteria. The 4'-acetylated-chrysomycin A and B had MICs of 0.5-2 μg ml and 2 to greater than 64 μg ml, respectively, toward Gram-positive bacteria including MRSA and VRE.
Trehalose is widely used as a sweetener, humectant, and stabilizer, but is ubiquitously degraded by the enzyme trehalase expressed in a broad variety of organisms. The stability of the new trehalose analogues lentztrehaloses A, B, and C in microbial and mammalian cell cultures and their pharmacokinetics in mice were analyzed to evaluate their potential as successors of trehalose. Among the 12 species of microbes and 2 cancer cell lines tested, 7 digested trehalose, whereas no definitive digestion of the lentztrehaloses was observed in any of them. When orally administered to mice (0.5 g/kg), trehalose was not clearly detected in blood and urine and only slightly detected in feces. However, lentztrehaloses were detected in blood at >1 μg/mL over several hours and were eventually excreted in feces and urine. These results indicate that lentztrehaloses may potentially replace trehalose as nonperishable materials and drug candidates with better bioavailabilities.
The NpmA bacterial 16S rRNA methyltransferase, which is identified from Escherichia coli strains, confers high resistance to many types of aminoglycoside upon its host cells. But despite its resistance-conferring ability, only two cases of its isolation from E. coli (14 years apart) have been reported to date. Here, we investigated the effect of the npmA gene on aminoglycoside resistance in Pseudomonas aeruginosa and Klebsiella pneumoniae and its stability in E. coli cells by comparing it with armA, another 16S rRNA methyltransferase gene currently spreading globally. As a result, we found that npmA conferred resistance to all types of aminoglycoside antibiotics we tested (except streptomycin) in both P. aeruginosa and K. pneumoniae, as well in E. coli. In addition, co-expression of armA and npmA resulted in an additive effect for the resistance. However, in return for the resistance, we also observed that the growth rates and the cell survivability of the strains transformed with the npmA-harboring plasmids were inferior than those of the control strains and that these plasmids were easily disrupted by IS10, IS1, and IS5 insertion sequences. We discuss these data in the context of the threat posed by pathogenic strains possessing npmA.
We have accomplished the total synthesis, structure determination, and biological evaluation of pargamicin A and one of its diastereomers. Two key tripeptide segments were synthesized using a linear peptide elongation process that includes the direct coupling of a poorly nucleophilic piperazic acid derivative. The resulting tripeptides were coupled using triphosgene/collidine at ambient temperature leading to a precursor for the final cyclization step. T3P‐promoted macrolactamization under high‐dilution conditions, followed by the removal of the benzyl protecting group was used to furnish two putative structures of pargamicin A. Comparison of the 1H and 13C NMR spectra and the antibacterial activity of the natural and synthetic products successfully revealed that the absolute configuration of the N‐hydroxy‐Ile residue of pargamicin A is 2S,3S. A biological evaluation of synthetically obtained pargamicin A and its diastereomer suggested that the stereostructure of the cyclic peptide scaffold of the natural product plays a crucial role in determining the strength of its antibacterial activity.
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