Resistance to Azoles

Azoles are the antifungal agents widely used to

treat a variety of fungal infections.

Development of resistance to azoles has become

an increasingly important problem affecting the
management of patients suffering from fungal
infections.
Mechanism of action of azoles

Azoles are the inhibitors of fungal cytochrome

P450 3A enzyme lanosterol 14α-demethylase
and thus prevent the conversion of lanosterol
to ergosterol.

This can lead to the deficiency of ergosterol (a

regulator of fungal cell membrane fluidity and
aysmmetry) and accumulation of sterol
precursors

As a result of ergosterol depletion, integrity and

function of fungal cell membrane is disrupted,
eventually leading to cell lysis [1]
 Acetyl CoA

Squalene

Squalene-2,3-oxide

Lanosterol
Azoles 14-α-demethylase

Ergosterol
Virulent gene involved in the resistance
to azoles
Pathogenic fungi can overcome the inhibition of azoles
by increasing the content of the target enzyme
molecules, either by gene amplification or by over
expression of corresponding gene ERG11
ERG11 overexpression is relatively common in C. albicans
with two main mechanisms
1. Formation of an isochromosome with two copies of the left
arm of chromosome 5 (i(5 L)), in which ERG11 resides or
by duplication of entire chromosome leading to gene
amplification
2. Activating mutations in the gene encoding the transcription
factor upc2, which results in over expression of ERG11 [2]
Molecular Mechanism of Azoles
resistance

At molecular level different mechanisms contribute to the

resistance against azoles antifungal drugs
These mechanisms include

Modification of antifungal target ( lanosterol demethylase)

Decreased drug accumulation inside the fungal cell due to
over expression of multidrug efflux pump
Alteration in sterol biosynthesis
Deficiency in the uptake of azole derivative [3]
Biofilm formation [4]
Global Epidemiology
In Europe many countries including Belgium, France, Spain,
Denmark, Italy, Netherlands, Norway, Germany, Ireland, UK,
Poland, Romania and Austria have reported azoles resistance.
Resistance is also reported outside Europe I n Turkey , Iran,
Kuwait, Japan China, Taiwan, Pakistan, India, Tanzania and
Australia. [5]

World wide map of azoles resistance in A. fumigatus . The red highlighted countries
have reported azoles resistance
Possible solution to Azoles resistance

Invasive Candidiasis present an emerging global public health

challenges due to emergence of resistance to frontline
treatment options, such as fluconazole

Hence, the identification of other compounds capable of

pairing with fluconazole and averting azole resistance would
potentially prolong the clinical utility of this important group.

Sulfa Antibacterial drugs can be used for the purpose of

reversing azole resistance in Candida. These drugs have
abililty to restore fluconazole sensitivity in Candida
albicans . [6]
References

[1] Isabelle E. J. A 2006 mode of antifungal action and resistance development.

[2] Cowen LE et all 2014 Mechanism of antifungal drug resistance

[3] Ramage G et all 2009 Our current understanding of fungal biofilm

[4] Jose L. Lopez-Ribot et all 2017 Fungal drug resistance : azoles

[5] Jacques F. Meis 2016 Clinical implications of globally emerging azoles

resistance in Aspergillus fumigatus

[6] Hassan E. Eldesouky 2017 Reversal of Azole resistance in Candida

albiacans by Sulfa Antibacterial Drugs