Juntendo University, Tokyo, established in 1838.

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Department of Infection Control Science (ICS)

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1. The origin of methicillin resistance in Staphylococcus aureus (MRSA).

We discovered that S. aureus acquired methicillin-resistance gene mecA through the mobile genetic element called staphylococcal cassette chromosome mec (SCCmec) in 2000 (Fig. 1).  We also determined the first whole genome nucleotide sequence of MRSA in 2001.  The comparative structural analysis has corroborated that the oldest staphylococcal species S. fleurettii was the origin of the mecA gene.  A mecA homologue mecB has also been discovered in Macrococcus caseolyticus genome, suggesting mecA and its homologs were distributed in nature before staphylococcal colonization on mammalian hosts.

Fig 1
Fig 1. SCCmec is composed of mec-gene complex and ccr-gene complex.
Hiramatsu K, et al. Infect Chemother. 2013;45:117-36.
Tsubakishita S, et al. Antimicrob Agents Chemother 2010;54:1469-75.

2. Vancomycin resistance in S. aureus.

We discovered the first MRSA strain with vancomycin-intermediate resistance(VISA) in 1996, and uncovered its resistance mechanism by series of experiments since then. We clarified that enhanced synthesis of cell-wall peptidoglycan and reduced autolysis of the cell are the basic mechanism. Recently, we found a unique  phenotypic resistance to vancomycin called ‘slow VISA’ (sVISA). The strain assumes high-level resistance to vancomycin as long as vancomycin is present, but returns to susceptibility if vancomycin is withdrawn. This phenomenon explains the therapeutic failure of the infection caused by S. aureus whose vancomycin MIC values are in susceptible range (≤2mg/L). 
Hiramatsu K, et al. J Global Antimicrobial Resistance 2014;2:213-224.
Saito M, et al. Antimicrob Agents Chemother. 2014;58:5024-35.

3. Development of ‘Reverse Antibiotics'

By screening 1928 culture supernatants of Actinobacteria, we re-discovered nybomycin (NYB) that possessed a strong bactericidal activity against fluoroquinolone-resistant strains, whereas only a weak activity against susceptible strains. NYB-resistant mutants appear at low frequency, and all NYB resistant mutants were back mutated to the wild type, acquiring fluoroquinolone-susceptibility. Accordingly, we designated NYB as a novel class of antibiotic ‘Reverse Antibiotic (RA)’. RA is expected to break the vicious cycle between antibiotics and bacteria (Fig.2). NYB derivative substances have been developed and being evaluated for the future use in clinics.

Fig 2
Fig 2. Resolving the problem of multi-drug resistance by the use of RA
Hiramatsu K, et al. J Infect Chemother. 2014;20:593-601.
Hiramatsu K, et al. Int J Antimicrob Agents. 2012;39:478-85.

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