A D-octapeptide drug efflux pump inhibitor acts synergistically with azoles in a murine oral candidiasis infection model.
Clinical management of patients undergoing treatment of oropharyngeal candidiasis with azole antifungals can be impaired by azole resistance. High-level azole resistance is often caused by the overexpression of Candida albicans efflux pump Cdr1p. Inhibition of this pump therefore represents a target for combination therapies that reverse azole resistance. We assessed the therapeutic potential of the D-octapeptide derivative RC21v3, a Cdr1p inhibitor, in the treatment of murine oral candidiasis caused by either the azole-resistant C. albicans clinical isolate MML611 or its azole-susceptible parental strain MML610. RC21v3, fluconazole (FLC), or a combination of both drugs were administered orally to immunosuppressed ICR mice at 3, 24, and 27 h after oral inoculation with C. albicans. FLC protected the mice inoculated with MML610 from oral candidiasis, but was only partially effective in MML611-infected mice. The co-application of RC21v3 (0.02 μmol per dose) potentiated the therapeutic performance of FLC for mice infected with either strain. It caused a statistically significant decrease in C. albicans cfu isolated from the oral cavity of the infected mice and reduced oral lesions. RC21v3 also enhanced the therapeutic activity of itraconazole against MML611 infection. These results indicate that RC21v3 in combination with azoles has potential as a therapy against azole-resistant oral candidiasis.
Teikyo University Institute of Medical Mycology, Tokyo, Japan. m-mirjalili@sbu.ac.ir
Kazumi
K
Hayama
Hiroko
H
Ishibashi
Sanae A
SA
Ishijima
Kyoko
K
Niimi
Shigeru
S
Tansho
Yasuo
Y
Ono
Brian C
BC
Monk
Ann R
AR
Holmes
David R K
DR
Harding
Richard D
RD
Cannon
Shigeru
S
Abe
D000818:Animals; D002176:Candida albicans / Q000472:pathogenicity*; D002180:Candidiasis, Oral / Q000188:drug therapy* / Q000382:microbiology; D004195:Disease Models, Animal; D004338:Drug Combinations; D025141:Drug Resistance, Fungal; D004357:Drug Synergism; D015725:Fluconazole / Q000008:administration & dosage / Q000494:pharmacology*; D005656:Fungal Proteins / Q000037:antagonists & inhibitors*; D017964:Itraconazole / Q000008:administration & dosage / Q000494:pharmacology; D026901:Membrane Transport Proteins; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology; D014059:Tongue / Q000382:microbiology / Q000473:pathology
C094693:CDR1 protein, Candida albicans; D004338:Drug Combinations; D005656:Fungal Proteins; D026901:Membrane Transport Proteins; D009842:Oligopeptides; D017964:Itraconazole; D015725:Fluconazole