Question

Briefly describe an example of multiple drug resistance against azoles and echinocandins. (Indicate the name of the fungus and describe how the fungus is resistant to the drugs) 1/3 page.

Answer 1

Azoles (Ex. Cltrimazole, econazole, fenticonazole, miconazole, tioconazole etc) acts by inhibiting the Fungal cytochrome P450 3A enzyme, lanosine 14alpha demethylase which is responsible for converting lanosterol to ergosterol. The resulting depletion of ergosterol alters the fluidity of the membrane and interfere with the action of membrane associated enzymes which inturn affects the fungal replication

Echinocandins (Ex. Capsofungin) inhibit the synthesis of 1,3 Beta glucan a glucose polymer which is necessary for maintaining the structure of fungal cell wall

Squalene
lanosterol
	<--- Azoles
Ergosterol
Fungal cell membrane	<---- Echinocandins

Multiple drug resistance in fungus:

Candida species are fast developing multiple drug resistance against the Azoles and Echinocandins. The mechanism of drug resistance are:

1. Fungal cell walls are developing protein pumps in their membranes (Ex. Candida drug resistance CDR1, CDR2, Multidrug resistance pumps) which acts as efflux pumps by pumping the drugs from the cell membrane and thus evading the action of drugs

2. Azoles and Echinocandins exert their affect by binding to Erg-11 protein. Overexpression of Erg-11 gene due to point mutation in fungi led to the structural changes in Erg-11 which make the drug unable to bind to the protein and thus maintaining the integrity of the cell membrane.

They exhibit cross resistance to the azoles making the entire class of azoles ineffective in treatment. On the bright side the mechanism of resistance is not plasmid mediated as seen in bacteria (mechanism is transcriptional regualation) which means that the resistance is not transfered rapidly to other microorganisms.

Other problems in the fungal treatment are less number of drugs to treat fungal infections (when compared to bacterial treatment), echinocandins are not broad spectrum antifungals, eventhough some antifungals are effective they exhibit toxicity like polyenes binds to cholesterol and destructs it, azoles have interactions with many drugs.