Iminosugars, carbohydrate analogues that have a nitrogen atom in place of the carbohydrate ring oxygen atom, have attracted increasing interest as new glycomimetics. Gem-diamine 1-N-iminosugars, proposed by us as a new class of iminosugars, have a nitrogen atom in place of the anomeric carbon. Various kinds of 1-N-iminosugars have been synthesized from glyconolactones as a chiral source by the versatile synthetic strategy in a stereospecific fashion and/or by the convergent strategy from siastatin B, a secondary metabolite of Streptomyces. The protonated form of the 1-N-iminosugar mimics the charge at the anomeric position in the transition state of enzymatic glycosidic hydrolysis, resulting in the strong and specific inhibition for glycosidases and glycosyltransferases. They have recently been recognized as a new source of therapeutic drug candidate in a wide range of diseases associated with the carbohydrate metabolism of glycoconjugates such as tumor metastasis, influenza virus infection, inflammatory disease and so forth. This review describes our research progress in synthesis, biological and pharmacological activity, and the therapeutic potentials of gem-diamine 1-N-iminosugar (gem-diamine 1-azasugar).

Despite the dramatic progress of cancer research, cancer is a major cause of death in Japan, and development of effective therapeutic drugs is still needed. In recent years, molecular targeted therapeutic drugs targeting genes involved in cancer onset have greatly contributed to cancer treatment. In developing this molecular targeted drug, how to search for new drug target molecules and how to efficiently obtain the lead compound becomes a problem. Natural products have made a great contribution to the development of pharmaceutical development so far, accounting for about 60% of medicines approved in the past 30 years. Meanwhile, in recent years, the mainstream of drug development has shifted to synthetic compounds, and natural product screening tends to shrink. However, natural products are overwhelmingly dominant in terms of “structural diversity” and “Bioactive diversity” compared to synthetic compounds, therefore, natural products still have sufficient potential as a drug seed. We therefore conducted natural product screening in microorganisms to obtain the compounds that function as antitumor drug-seed. In this article, we describe the studies on the antitumor drug-seed from the microbial secondary metabolites we isolated.

Herpes simplex virus-2(HSV-2)is one of the most common sexually transmitted infections through genital epithelial cells followed by the establishment of latency in the sacral ganglia. So far, several pharmacological interventions are available to inhibit virus replication. However, HSV-2 has not been able to be completely cured by them. Furthermore, it’s been known that eonatal HSV-2 infection is seriously lethal without the treatment and HSV-2 infection in adults increases the susceptibility of high-risk HPV and HIV infection. Therefore, preventative vaccines or curative medicines are required for this disease. However, all of the current vaccine has been ineffective to prevent HSV-2 disease or infection despite inducing anti-HSV-2 immunity in the circulation. Towards developing vaccines to prevent HSV-2 transmission, a further understanding of the mechanism by which immune responses within peripheral tissues following HSV-2 infection are required. However, the immune mechanism of protection within the female genital mucosa and dorsal root ganglia(DRG)has been poorly understood. Until now, we have found that 1)genital tissue-resident immune response by establishing memory lymphocyte cluster (MLC)including HSV-2-specific T cell populations was required for preventing the spreading of HSV-2 from genital tissues to dorsal root ganglia(DRG)and 2)IFN-γ rapidly produced by circulating CD4⁺ memory T cells in DRG increased vascular permeability in blood-nerve barrier to allow the entry of anti-HSV antibody within neuronal tissues. Our results shed light on a previously unappreciated role of CD4⁺ memory T cells against genital herpes infection.

Allosamidin and aflastatin A are metabolites of Streptomyces. Allosamidin was isolated as the first chitinase inhibitor and used as a biological probe to investigate chitinase roles in not only chitin-containing organisms but also chitin-non-containing organisms. Allosamidin showed anti- asthmatic activity toward mammals. Furthermore, it showed promoting activity for chitinase production of Streptomyces, which suggested that allosamidin was a signal molecule controlling chitin metabolism and bacterial flora in soils. Aflastatin A was isolated by the first screening search for aflatoxin production inhibitors produced by microbes. Absolute structures of aflastatin A and its colleague, blasticidin A, were determined and their modes of action for inhibiting aflatoxin production were shown to inhibit protein synthesis by inhibiting a protein phosphatase. Based on studies on aflastatin A, many aflatoxin production inhibitors were found from other sources such as microbial metabolites and plant constituents.

Lasso peptides belong to the class of ribosomally assembled and post-translationally modified peptides in bacteria. They consist of a macrolactam ring comprised of 7 to 9 amino acid residues and a linear C-terminal peptide tail. The ring, formed between the N-terminal α-amino group and the carboxylic acid side chain of an Asp or Glu, is threaded by the C-terminal peptide tail. The fascinating topological and biological features of lasso peptides have attracted interest of many researchers for the decade. In this review, I summarize the overview of lasso peptides from the initial discovery up to the current state.

In Japan, antibiotic products, like vaccines, had been regarded as biological preparations. This is due to the fact that penicillin, the first antibiotic product, was a mixture of natural compounds produced by a microorganism. As a consequence, antibiotics were controlled under specific “minimum requirements” with special attention given to health and hygiene.

Individual “requirements” for antibiotic products, such as “The Minimum Requirements for Penicillin” enacted in May of 1947, and others, were compiled into “The Minimum Requirements for Antibiotic Preparations” in March of 1952. These were later modernized to “The Minimum Requirements for Antibiotic Products of Japan; MRAPJ” in August of 1969 by conforming to amendments of “The Japanese Pharmacopoeia; JP” and international scientific standards.

Quality control in Japan, based on the MRAPJ and national certification of antibiotic products, had prevented the distribution of low-quality preparations and even forgery products. As a result, high-quality preparations were used clinically for the treatment of life-threatening infections or neoplastic diseases and eventually contributed to maintaining the health of the population. It can further be adduced to be one of the contributing factors for the expansion of the average lifespan of Japanese(by approximately 31 years for women and 28 years for men)during the period from 1947 to 2000.

For medicinal products, quality standards and methods of testing are principally provided in the JP based on Article 41 of the Pharmaceutical Affairs Law. The MRAPJ, based on Article 42 of the Law, underwent three extensive revisions (in 1982, 1990, and 1998) in accordance with the amendments of the JP. In some exceptional cases novel methods of testing were adopted by the MRAPJ ahead of the JP. On the other hand, up to 63% of the entities listed in the 1998 MRAPJ were manufactured via chemical synthetic processes and thought to have low necessity for controlling care with regard to special attention under the category of health and hygiene. In 1999, an administrative decision was made to integrate the MRAPJ into the JP and the work of transferring the monographs of antibiotic products from the MRAPJ to the JP started in 2000.

In this report, we describe the pharmaceutical and historical aspects, details and characteristics of the quality control of antibiotic products in Japan from investigations and analyses on enactment, and the subsequent amendments of the MRAPJ. This particular report will also introduce the integration work up to its preparation stage, but details regarding the integration of the MRAPJ into the JP will be discussed in our following article.

Group B Streptococcus (GBS, or Streptococcus agalactiae) is among the most common causes of severe bacterial infections in early infancy. Combination therapy with ampicillin (AMP) plus gentamicin (GM) is recommended for such GBS infections, although this therapeutic approach has been based on relatively old in vitro and in vivo studies. Recently, a synergistic effect from this combination was found to involve ribosomal binding by GM allowed to enter bacterial cells by cell wall damaged from AMP. Here we report a 2-month-old boy with meningitis caused by GBS, against which AMP plus GM proved clinically effective. GBS isolated from his cerebrospinal fluid and blood belonged to capsular type III and sequence type 17, and possessed hypervirulent GBS adhesin (HvgA); GBS isolated from maternal vaginal samples was the same type. In vitro determinations of time-kill kinetics forthe patient’s isolate showed enhancement of bactericidal activity by combining AMPwith a small amount of GM. This case report provides clinical and laboratory evidence supporting effectiveness of combination therapy of AMP plus GM for severe GBS infection in early infancy.

Mycobacterium heckeshornense is rarely isolated from a clinical sample. We report a case of a patient with polymyositis in whom a deep abscess formed in the gluteus maximus muscle and in which M. heckeshornense was identified by DNA sequencing. Combination therapy of levofloxacin and clarithromycin for 2 years improved inflammatory findings and 5 years have passed without recurrence of the gluteal abscess. Identification of the bacterial strain in nontuberculous mycobacterium (NTM) infection is important to determine the treatment plan and accumulation of data on drug sensitivity is required to establish a therapeutic strategy for rare pathogen such as M. heckeshornense.