Synergistic interaction of fluconazole/sodium bicarbonate on the inhibition of <i>Candida glabrata</i> phospholipase gene

Hosseini, Seyed Mohammad Karim; Alizadeh, Fahimeh; Nouripour-Sisakht, Sadegh; Khodavandi, Alireza

doi:10.1590/s2175-97902022e19897

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Article • Braz. J. Pharm. Sci. 58 • 2022 • https://doi.org/10.1590/s2175-97902022e19897 copy

Synergistic interaction of fluconazole/sodium bicarbonate on the inhibition of Candida glabrata phospholipase gene

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Candida glabrata infections are responsible for deaths of people globally. Fluconazole is known to be less effective against C. glabrata, which developed many strategies to evade being destroyed by fluconazole. To achieve enhanced efficacy of fluconazole against C. glabrata, the interaction of fluconazole with sodium bicarbonate was investigated using the CLSI guidelines. The efficacy of fluconazole alone and in combination with sodium bicarbonate was evaluated using the time-kill and phospholipase production assays. Eventually, the expression of PLB was assessed using semi-quantitative RT-PCR to investigate the inhibitory properties of fluconazole alone and in combination with sodium bicarbonate against C. glabrata. The fluconazole/sodium bicarbonate combination displayed synergistic and antagonistic effects (FICI= 0.375-4.25). In C. glabrata ATCC, SN 152, and SN 164, the fluconazole/sodium bicarbonate combination exhibited a significant fungicidal activity (p< 0.05) but antagonistic effect in the case of SN 283. With exception of SN 283, a significant reduction was noted in phospholipase production in clinical isolates of C. glabrata treated with fluconazole/sodium bicarbonate combination. The PLB was down-regulated significantly by 0.168-0.515 fold in C. glabrata treated with fluconazole/sodium bicarbonate. The results suggested fluconazole/sodium bicarbonate to have a potential synergistic interaction in C. glabrata, and the underlying mechanism may be associated with phospholipase gene.

Keywords:
Candida glabrata; Fluconazole; PLB; Sodium bicarbonate

Primer	Orientation	Sequence	Length (bp)	NCBI GenBank accession number
PLB	Forward	5' ATGGCTGGTCTTTCTGGTGG 3'	839	AF498582
PLB	Reverse	5' AGGTCACGCTCTTGCTTCAA 3'	839	AF498582
Actin	Forward	5' GTTGACCGAGGCTCCAATGA 3'	384	FN394020
Reverse	5' TGAGCAGCGGTTTGCATTTC 3'		384	FN394020

Code	Antibiotic name	Antibiotic class	Breakpoints	%R	%I	%S	%R 95%C.I.	Geom. Mean	MIC Range	MICs (%)
Code	Antibiotic name	Antibiotic class	Breakpoints	%R	%I	%S	%R 95%C.I.	Geom. Mean	MIC Range	SN 152	SN 164	SN 283
FLU_NM	Fluconazole	Antifungals	S<=2 R>=8	33	0	67	1.8-87.5	2.52	0.5 - 16	2 (33.3)	16 (33.3)	0.5 (33.3)

Isolates/ Antifungal	Fluconazole	Sodium bicarbonate	Fluconazole/Sodium bicarbonate
Isolates/ Antifungal	MIC	MIC	MIC	FICI	Interpretation
C. glabrata ATCC 90030	2	3152	0.25/782	0.373	Synergism
SN 152	2	6250	0.5/1562	0.499	Synergism
SN 164	16	25000	2/6250	0.375	Synergism
SN 283	0.5	25000	2/6250	4.25	Antagonism

Antifungals/ Isolates		C. glabrata ATCC 90030	SN 152	SN 164	SN 283
Fluconazole	Untreated control	0.55±0.013^a	0.57±0.015^a	0.56±0.011^a	0.58±0.014^a
	2× MIC	0.87±0.016^e	0.86±0.014^e	0.59±0.019^c	0.88±0.019^e
	1× MIC	0.86±0.011^d	0.86±0.011^d	0.59±0.018^c	0.87±0.010^d
	½× MIC	0.85±0.018^c	0.85±0.013^c	0.58±0.013^b	0.85±0.010^c
	¼× MIC	0.84±0.015^b	0.84±0.012^b	0.58±0.015^b	0.83±0.013^b
Sodium bicarbonate	Untreated control	0.55±0.013^a	0.57±0.015^a	0.56±0.011^a	0.58±0.014^a
	2× MIC	0.84±0.016^d	0.86±0.010^e	0.84±0.010^d	0.85±0.011^d
	1× MIC	0.83±0.012^c	0.84±0.018^d	0.83±0.012^c	0.83±0.011^c
	½× MIC	0.82±0.011^b	0.82±0.010^c	0.82±0.012^b	0.82±0.011^b
	¼× MIC	0.82±0.010^b	0.81±0.019^b	0.82±0.010^b	0.82±0.017^b
Fluconazole/Sodium bicarbonate	Untreated control	0.55±0.013^a	0.57±0.015^a	0.56±0.011^a	0.58±0.014^a
	2× MIC	0.93±0.015^d	0.96±0.010^d	0.92±0.010^c	0.59±0.010^b
	1× MIC	0.91±0.014^c	0.95±0.014^c	0.92±0.012^c	0.59±0.010^b
	½× MIC	0.88±0.011^b	0.94±0.010^b	0.90±0.015^b	0.58±0.010^a
	¼× MIC	0.88±0.011^b	0.94±0.010^b	0.90±0.010^b	0.58±0.013^a

Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Av. Prof. Lineu Prestes, n. 580, 05508-000 S. Paulo/SP Brasil, Tel.: (55 11) 3091-3824 - São Paulo - SP - Brazil
E-mail: bjps@usp.br

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[1] *Correspondence: F. Alizadeh (ORCID: https://orcid.org/0000-0002-7074-0464). Department of Microbiology. Yasooj Branch. Islamic Azad University, Yasooj, Iran. Phone: +987433313930. E-mail: mnalizadeh@yahoo.com. S. Nouripour-Sisakht (ORCID: https://orcid.org/0000-0002-1158-4318). Cellular and Molecular Research Center. Yasuj University of Medical Sciences. Yasuj, Iran. A. Khodavandi. ORCID: https://orcid.org/0000-0001-9498-9822.