The history of developing in discovery of antimicrobial agents in Japan started with the chemical studies and in vitro studies at first and then transited with the studies by genomic researches. The antimicrobial agents used clinically in Japan consist from β-lactam type, quinolone type, macrolide type, aminoglucoside type, glycopeptide type, streptogramin type, oxazolidinone type, and others. Among these type of antimicrobial agent, the drugs in which the developing in drug discovery continues still are mainly oral and injectable cephems, oral and injectable carbapenems, oral and injectable quinolones and ketolides. In drug discovery by genomic researches, the essential genes for bacterial living are regarded as the target of drug discovery. In order to find the examples for the target of drug discovery by genomic research, we searched the reports in Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) held on 2002 and 2003. Among these reports, we could found many inhibitors of various steps that are essential for bacterial living. As the typical inhibitor, the peptide deformylase inhibitor (PDF) was observed and the exclusive session for PDF could be found.

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Complete genome sequences of major pathogenic bacteria have been disclosed and available in the public domain for a number of years now, so we can consider ourselves in the post-genomic era. Bacterial genome information has been widely used in research to support the search for new antibacterial agents by validating new targets for antibacterial agents, by analysing the distribution of these targets among species and by surveying trends in the emergence of resistance mutants. Moreover, we can utilize information taken from bacterial genomes to analyze drug-target interactions based on structural details of the target protein deduced from its gene sequence and associated in silico screening for potential inhibitors against the target protein. In our research efforts on quinolones and efflux pump inhibitors, we have used genome information to assess the target distribution, to analyze trends in resistance development and to estimate the effect of target inhibition. Recently, protein crystallization technology has improved greatly, even for membrane-associated proteins, and therefore a structural biological approach may possibly assist in the discovery of new lead compounds that inhibit proteins which were impossible to study in the past.

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β-lactamases acquire substrate spectrum extension by mutating residues at the substrate-binding site, whereas penicillin-binding proteins reduce the affinity with β-lactams by mutating residues at this site. Alteration in the recognition of β-lactams by these penicillin-interacting enzymes must be clarified and new βlactams designed that have high affinity with penicillin-binding proteins and are stable against extended spectrum β-lactamases. Based on crystal structures of penicillin-binding proteins and β-lactamases, we can deduce the roles of residues at the substrate-binding site and design new β-lactams. With the aid of computationalmethods, faropenem, a 5, 6-trans-penem, was converted to 5, 6-cis-penems that show anti-MRSA activity and stability against β-lactamases.

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Macrolide antibiotics are classified by the size of the macrocyclic lactone ring of aglycone as 12-, 14-, or 16-membered ring macrolides. A number of macrolide antibiotics, such as erythromycin (EM), oleandomycin, leucomycin, spiramycin, josamycin, midecamycin and their derivatives, have been used extensively in human medicine, especially against a wide range of gram-positive bacteria. They have seen only limited activity, however against most gram-negative bacteria. Some are active against Legionella pneumophila, Rickettia strains, Spirochaeta, large viruses, protozoa, Toxoplasma, and Mycoplasma. Recently, macrolide antibiotics have showen some novel action. First, EM showed dramatic gastrointestinal motor-stimulating activity, and the genetic name “motilide” was proposed for a series of macrolides having motilin-agonistic activity. Second, the prognosis of diffuse panbronchiolitis (DPB), an incurable chronic inflammatory airway disease, improved significantly by treatment with long-term, low-dose EM. Such therapeutic efficacy is assumed to be due to antiinfl ammatory or immunomodulatory activity by macrolide antibiotics. Third, macrolide antibiotics showed the modulation of bacterial functions such as the inhibition of biofilm formation and the inhibition of the expression of virulence factors at sub-MIC concentrations.

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Susceptibility test results obtained by the Mycobacteria Growth Indicator Tube 960 SIRE susceptibility test (MGIT960 SIRE, Nippon Becton Dickinson Co., Ltd.), a kit for rapid automated susceptibility testing for Mycobacterium tuberculosis, for MGIT960 with liquid medium were compared to those by 1% Ogawa medium (conventional) and proportion method (NCCLS). The four drugs tested were streptomycin, isoniazid (INH), rifampicin (RFP), and ethambutol. Fifty-two strains of Mycobacterium tuberculosis isolated from patients with tuberculosis were used as test strains.
Susceptibility test results obtained by these three methods, all coincided in 92.3% to 96.2% of strains, which showed favorable coincidence although they depended on these drugs. Strains suspected of multidrug-resistant Mycobacterium tuberculosis (MDR-TB) resistant to INH and RFP were three (5.8%) for MGIT960 SIRE and one (1.9%) for NCCLS but none were detected by the 1% Ogawa medium. The mean time required for the susceptibility test was 7.8 days for MGIT960 SIRE, 10.1 days for the 1% Ogawa medium, and 21.0 days for NCCLS method. Susceptibility test results were thus obtained most rapidly by MGIT960 SIRE.
MGIT960 SIRE is useful for determining the susceptibility of Mycobacterium tuberculosis to antibiotics since test results coincide well with those obtained by 1% Ogawa medium and NCCLS, which are used widely in Japan, and test results are rapidly obtained by MGIT960 SIRE. This makes it possible to detect MDR-TB rapidly, speeding up time to treatment.

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