title: T-2307 shows efficacy in a murine model of Candida glabrata infection despite in vitro trailing growth phenomena.
abstract: T-2307, a novel arylamidine, has been shown to exhibit broad-spectrum in vitro and in vivo antifungal activities against clinically significant pathogens. In our preliminary studies, Candida glabrata exhibited significant trailing growth (partial inhibition of growth over an extended range of antifungal concentrations) in the presence of T-2307 when it was tested using the Clinical and Laboratory Standards Institute (CLSI) guidelines with 0.2% glucose and 48 h of incubation, making reading of the MIC difficult. In the present study, we attempted to attenuate trailing growth to avoid misreading of the MIC. On the basis of the hypothesis that T-2307 may inhibit the mitochondrial functions of cells, the carbon source or the glucose concentration in the medium was changed. The trailing growth of C. glabrata ATCC 90030 in the presence of T-2307 was attenuated as the concentration of glucose in the medium decreased to 0.1% or lower, and trailing growth was completely inhibited when glycerol was used. A susceptibility test using Alamar blue was performed to facilitate reading of the MIC without changing the composition of the medium and provided a clear MIC endpoint at 24 h. To investigate if T-2307 shows efficacy against trailing isolates in vivo, we evaluated the efficacy of T-2307 in a murine model of disseminated candidiasis caused by C. glabrata. T-2307 at 0.05 mg/kg of body weight/day significantly decreased the viable count in the kidneys compared to that for the control group (P < 0.05). It would be better to test the susceptibility of C. glabrata to T-2307 using modified media or Alamar blue to avoid misreading of the MIC due to the significant trailing growth.
authors.affiliation: Research Laboratories, Toyama Chemical Co., Ltd., 2-4-1 Shimookui, Toyama 930-8508, Japan. eio_yamada@toyama-chemical.co.jp
authors.forename: Eio
authors.initials: E
authors.lastname: Yamada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishikawa
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Nomura
authors.forename: Junichi
authors.initials: J
authors.lastname: Mitsuyama
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D041221:Candida glabrata / Q000187:drug effects / Q000502:physiology*; D002177:Candidiasis / Q000188:drug therapy / Q000382:microbiology; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure
chemical_list: D000935:Antifungal Agents