Laboratory of Medicinal Chemistry

Research Outline

The predecessor of our laboratory was the Institute of Bioorganic Chemistry, established in Hiyoshi in 1974. It was renamed the Hiyoshi Medicinal Chemistry Research Institute as an affiliate to the Microbial Chemistry Research Center in 2003 and was renamed again as the Institute of Microbial Chemistry, Hiyoshi in 2010. The current Laboratory of Medicinal Chemistry started in accordance with the transfer to the new research building of the Institute of Microbial Chemistry in 2015. Since its establishment, we have continuously conducted studies on the synthetic chemistry of antibiotics.

Theme outline

1. Synthetic study of aminoglycoside antibiotics

We have synthesized a large number of kanamycin derivatives based on the drug resistance mechanisms of kanamycin-resistant bacteria and examined their antibacterial activity against resistant strains. Our on-going studies have led the way for designing and synthesizing aminoglycosides with improved activity against resistant bacteria. Furthermore, basic studies of sugar chemistry, such as deoxygenation and fluorination, and regioselective protection of the amino or hydroxyl groups of aminoglycosides have been conducted at this institute. Through these studies, we have succeeded in developing the antibacterial chemotherapeutic agent dibekacin and the anti-MRSA drug arbekacin. In addition to kanamycins, many aminoglycoside antibiotics, such as streptomycin and neomycin C, were completely synthesized at this institute.

Recently, we synthesized a fourth generation kanamycin derivative, 2-OH-ABK, displaying less toxicity and excellent antibacterial activity. This compound is expected to develop as a core drug in combination therapy against severe infectious diseases because of its excellent properties.

Fig.1 Structures of aminoglycoside antibiotics.
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2. Development of new macrolide antibiotics

Fig.2 Structure of tildipirosin.
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Our institute has undertaken extensive studies on the chemical modifications of 16-membered macrolide antibiotics. This research has led to the development of semisynthetic macrolide antibiotics that are remarkably active against Gram-negative bacteria, although standard macrolide antibiotics are inactive against them.

Recently, tildipirosin (20, 23-dipiperidinomycaminosyl tylonolide) was derived from tylosin in our laboratory and was found to exhibit strong antimicrobial activity against Mannheimia haemolytica and Pasteurella multocida, which cause bovine respiratory disease (BRD). In a joint development project (duration, six years) with a foreign pharmaceutical company, this compound was proved to be safe and effective against bovines with pneumonia in the field tests conducted in Europe and the United States. This compound was marketed on a global scale from 2013 as an antimicrobial animal drug (brand name, ZUPREVO).

3. Discovery of a novel antituberculosis drug CPZEN-45

    Fig.3 Structure of CPZEN-45.
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    Fifty years after the first tuberculosis (TB) drugs were introduced, TB remains one of the deadliest human diseases, killing over 1.5 million people worldwide each year. The recent increase in MDR-TB, XDR-TB, and refractory TB in AIDS patients is one of the most important issues for worldwide public health.

    In 2003, we discovered the anti-TB antibiotics caprazamycins, which are produced by the Actinomycete strain Streptomyces sp. MK730-62F2. Subsequently, we found that some of the derivatives from caprazamycin exhibited potent and selective activities against Mycobacterium tuberculosis H37Rv in vitro and have excellent water solubility, which is superior to the parent compound. In particular, CPZEN-45 exhibited good activity against MDR- and XDR-TB strains in vitro and showed excellent therapeutic efficacy in the treatment of mice infected with XDR-TB.

    Analysis of the mode of action revealed that CPZEN-45 exhibits antitubercular activity by inhibiting the activity of the WecA transferase, involved in the biosynthesis of the cell envelope. This mechanism is different from any other currently used remedies, implying that CPZEN-45 would be effective against most of MDR-TB strains. CPZEN-45 is, therefore, undergoing pre-clinical trials as a drug against multidrug-resistant TB.

4. Synthetic study of lipopeptide antibiotic Tripropeptin C derivatives

The emergence and widespread frequency of multiple drug-resistant bacteria have made the treatment of bacterial infections increasingly difficult. MRSA and VRE have been an exceptionally serious problem in nosocomial infections. Therefore, the development of effective drugs having a new mode of action against these drug-resistant pathogens is urgently required.

Tripropeptin C for example, a novel cyclic lipodepsipeptide antibiotic, was found to be a promising novel class of antibiotic for the treatment of MRSA and VRE because of its excellent antibacterial activity and novel mechanism of action. Structure–activity relationship studies of Tripropeptin C are being conducted to produce promising derivatives.

Fig.4 Structure of tripropeptin C.
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