A novel polyamide SL-A92 as a potential fungal resistance blocker: synthesis and bioactivities in Candida albicans.
OBJECTIVE
To synthesize a novel polyamide SL-A92 and evaluate its bioactivity against drug resistance in Candida albicans.


METHODS
SL-A92 was synthesized using N-hydroxybenzotriazole (HOBT)/N,N'-dicyclohexylcarbodiimide (DCC) in solution phase. Its antifungal activities and effects on strain growth were tested using the micro-broth dilution method and growth curves, respectively. Induced drug resistance in the C. albicans collection strain SC5314 was obtained by incubation with fluconazole (12 microg/mL) for 21 passages. Meanwhile, incubations with SL-A92 plus fluconazole were also carried out in SC5314 strains, and the MIC(80)s were used to evaluate the inhibitory effects of SL-A92 on drug resistance during the induction process. Real time RT-PCR was performed to investigate the CDR1 and CDR2 mRNA levels in induced SC5314 strains.


RESULTS
SC5314 strain induced by the combination of fluconazole and SL-A92 (200 microg/mL) did not develop drug resistance. On day 24, the CDR1 and CDR2 mRNA levels in SC5314 strain co-treated with fluconazole and SL-A92 relative to fluconazole alone were 26% and 24%, respectively, and on day 30 the CDR1 and CDR2 mRNA levels were 43% and 31%, respectively.


CONCLUSIONS
SL-A92 can block the development of drug resistance during the fluconazole induction process, which partially results from the down-regulation of CDR1 and CDR2.
Zhu
Shao-long
SL
Department of Pharmacology, Second Military Medical University, Shanghai.
Jiang
Zhi-hui
ZH
Gao
Ping-hui
PH
Qiu
Yue
Y
Wang
Liang
L
Jiang
Yuan-ying
YY
Zhang
Da-zhi
DZ
D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D025141:Drug Resistance, Fungal / Q000187:drug effects*; D015725:Fluconazole / Q000494:pharmacology; D005656:Fungal Proteins / Q000187:drug effects / Q000235:genetics; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000235:genetics; D008826:Microbial Sensitivity Tests; D009757:Nylons / Q000138:chemical synthesis / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000935:Antifungal Agents; C094693:CDR1 protein, Candida albicans; D005656:Fungal Proteins; D007093:Imidazoles; D026901:Membrane Transport Proteins; D009757:Nylons; D012333:RNA, Messenger; C553168:SL A92; D015725:Fluconazole