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Institute of Microbial Chemistry, Hiyoshi, originally named “Institute of Bioorganic Chemistry” was established in 1974. Since reshuffling in 2003, the institute had been called “Hiyoshi Medicinal Chemistry Research Institute” as an affiliate to the Microbial Chemistry Research Center until May 2010. Since its establishment, we have continuously conducted studies on the synthetic chemistry of antibiotics.
1. Synthetic study of aminoglycoside antibiotics
We 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. The clinically useful antibiotic dibekacin was synthesized from kanamycin B at Sumio Umezawa’s laboratory (Department of Applied Chemistry, Faculty of Engineering, Keio University; the predecessor of this institute).
Our continuous study has led the way to design and synthesize aminoglycosides having improved activity against resistant bacteria. Furthermore, basic studies of sugar chemistry such as deoxygenation, fluorination, and selective reactions of the amino and hydroxyl groups of aminoglycosides have been conducted at this institute. Among these, regioselective protection of amino groups utilizing zinc chelates was applied to the industrial mass production of arbekacin. In addition to kanamycins, many aminoglycoside antibiotics such as streptomycin and neomycin C were completely synthesized at this institute.
We now focus our attention toward the development of novel aminoglycoside antibiotics with less toxicity to cure severe infectious diseases.
2. Synthetic study on macrolide antibiotics
Our institute has undertaken extensive studies on the chemical modifications of tylosin, a 16-membered macrolide antibiotic. 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. The compound was marketed 2011.
3. Synthetic study on new anti-tuberculosis drugs
Fifty years after the first tuberculosis (TB) drugs were introduced, TB still remains one of the deadliest human diseases, killing over 1.5 million people worldwide each year. The recent increase in multidrug-resistant TB (MDR-TB), extremely drug-resistant TB (XDR-TB), and refractory TB in AIDS patients is one of the most important issues for worldwide public health.
Our institute has previously identified a mixture of structurally analogous caprazamycins and novel lipo-nucleosides with various different alkyl side-chains in a culture broth of Streptomyces sp. MK 730-62F2. Its major component, caprazamycin B, showed good in vitro activity against drug-susceptible and multidrug-resistant M. tuberculosis strains. Furthermore, its mode of action was determined to be different from those of current anti-TB drugs.
Several derivatives of caprazene bearing a core structure of caprazamycin B were synthesized and evaluated for their antibacterial activity. CPZEN-45, a 4-butylanilide of caprazene, particularly exhibited excellent activity against drug-susceptible and drug-resistant M. tuberculosis. It showed excellent therapeutic efficacy in mice infected with XDR-TB.
The preclinical trials of this compound are underway.
4. Synthetic study on cyclic lipopeptide antibiotics
Although vancomycin and teicoplanin are frequently used as effective antibiotics against methicillin-resistant Staphylococcus aureus (MRSA), which is most commonly responsible for hospital-acquired infections, the number of resistant and low sensitive strains against these drugs has increased in recent times. Therefore, there is a need to develop novel antibiotics against MRSA.
Tripropeptin C, a lipopeptide antibiotic produced in a culture broth of Lysobacter sp. BMK333-48F3, was discovered at our institute; it exhibited good antibiotic activity against MRSA.
Structure–activity relationship (SAR) studies are now being conducted using the derivatives of this compound.
