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Date: 2009-02-13  Read: 13350

Dr. Keiichi Hiramatsu
Juntendo University
Tokyo, Japan

With the clinical use of penicillin G since 1940s, Staphylococcus aureus, one of the human natural flora has started to exhibit its extraordinary ability of adaptation to the environment. First, it conquered penicillin G and its derivatives by acquiring the plasmid encoding penicillinase. After the success of chemists to semi-synthesize the penicillinase-resistant penicillins (methicillin, oxacillin etc) and subsequent discovery of naturally penicillinase-resistant cephalosporins in 1960s, S. aureus again survived its hardship and prevailed all over the world as the methicillin-resistant S. aureus (MRSA). MRSA has acquired resistance to practically all the antibiotics so far developed in the past half century. Remaining therapeutics in the turn of the century were only some including vancomycin, linezolid, and daptomycin. Although several antibiotics are in the pipeline, we cannot predict how long the new agents would remain effective after they are launched.  However, we have to continue our efforts to develop new agents to counter MRSA infection since the effectiveness of the last group of antibiotis has gradually been crumbling. Vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA) have been reported, and linezolid-resistant MRSA has also been documented. Daptomycin tends to have less activity towards VISA clinical strains since the mechanism of resistance is partially overlapped between daptomycin and vancomycin resistance. In this case, the physiology of the vancomycin-, and daptomycin-resistant cells was drastically changed by sequential incorporation of mutations in the S. aureus regulatory genes. High-level methicillin resistance, as seen in certain MRSA strains which show extremely high MIC values with practically all beta-lactam antibiotics, is also a result of mutation.

Although we may seem to be fighting a losing battle with the tenacious organism, but the last century has brought us a big scientific technology to approach this problem. Spontaneous mutation and horizontal gene transfer are the two ways by which S. aureus acquires resistance to new antibiotics.

Having learned that, we should try novel strategies to counter MRSA infection. Firstly, we try to develop new antibiotics by taking advantage of the information obtained by recent vast amounts of research done using the information uncovered by S. aureus whole genome sequencing. We now know the blueprints of the creature whose ability is evidently restricted by the repertoire of its functional genes. Essential genes for their survival have been listed up as new targets of antimicrobial agents. Another strategy is to suppress the transfer of resistance genes across the barrier of species or even genera of bacteria. By determining the whole genome sequence of a strain of Macrococcus caseolyticus we found an ancestral form of mecA-gene complex, the genetic basis for MRSA. Macrococcus is closely related to genus Staphylococcus, but branched from the common ancestor before the speciation of staphylococcal species. It is more closely related to the group of gram-positive bacteria such as Enteroccus and Bacillus species than Staphylococcal is. The Macrococcus are frequently isolated from livestock. We recently identified an archaic form of mecA-gene complex on a plasmid harbored by such Macrococcus strains. It seems that methicillin resistance gene has also been prepared in the animal farm as the other resistance genes, such as vanA, were in the past. 

We expect emergence of many more CA-MRSA strains from Asian countries.  I really hope that ANSORP, as it did in the past decade, continues encouraging our Asian researchers to tackle incessantly with this everlasting problem of antibiotic chemotherapy.

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