Antifungal Effects of New Synthetic Materials, KAF-200522 and KAF-200522-HCl, on in vitro and in vivo Models / 한국실험동물학회지

KAF-200522 and its chloride form, KAF-200522-HCl, were invented in Chemon inc. as new triazole antifungal agents with excellent activities in vivo and in vitro against wide range of fungi. As a result of in vitro susceptibility measurements, 80% minimum inhibitory concentrations (MIC80) of both test articles against Candida albican sp. and Aspergillus fumigatus sp. were below 0.0156 microg/mL, which were over 4,100 times lower than those of fluconazole against fluconazole resistant C. albican sp. and A. fumigatus sp., and were over 16 times lower than those of amphotericin B against above same fungi. Additionally, against representative dermatophytes, Trichophyton sp., the MIC80s of both test articles were below 0.0156 microg/mL which were over 64 times lower than those of fluconazole and amphotericin B. As in vivo antifungal activities in A. fumigatus sp. infected mouse models, KAF-200522 treatment group at 600 mg/kg showed 80% survival rate which was 2 times higher than that of amphotericin B and showed 13.7 days in the mean survival time (MST) which was about 2.1 times higher than that of amphotericin B. But in KAF-200522-HCl treatment groups, all animals were found dead in contrast to 40% survival rate in amphotericin B treatment group, however dose dependent increases in MST was revealed. In conclusion, antifungal activities of KAF-200522 and its mimics, KAF-200522-HCl in vitro and in vivo were confirmed in this study, therefore the potentiality of the present compounds to be developed into new antifungal drug was expected.

Why do antimicrobial agents become ineffectual?

Antibiotic resistance has evolved over the past 50 years from a merely microbiological curiosity to a serious medical problem in hospitals all over the world. Resistance has been reported in almost all species of gram-positive and -negative bacteria to various classes of antibiotics including recently developed ones. Bacteria acquire resistance by reducing permeability and intracellular accumulation, by alteration of targets of antibiotic action, and by enzymatic modification of antibiotics. Inappropriate use of an antibiotic selects resistant strains much more frequently. Once resistant bacteria has emerged, the resistance can be transferred to other bacteria by various mechanisms, resulting in multiresistant strains. MRSA is one of the typical multiresistant nosocomial pathogens. A study of the PFGE pattern of endonuclease-digested chromosomal DNA showed that MRSA of a few clones were disseminated among newborns in the NICU of a Japanese hospital. In this regard, it is important to choose appropriate antibiotics and then after some time, to change to other classes to reduce the selection of resistant strains. Since the development of epoch-making new antibiotics is not expected in the near future, it has become very important to use existing antibiotics prudently based on mechanisms of antibiotic action and bacterial resistance. Control of nosocomial infection is also very important to reduce further spread of resistant bacteria.