Antifungals targeted to protein modification: focus on protein N-myristoyltransferase.

Invasive fungal infections have increased dramatically in recent years to become important causes of morbidity and mortality in hospitalised patients. Currently available antifungal drugs for such infections essentially have three molecular targets: 14α demethylase (azoles), ergosterol (polyenes) and β-1,3-glucan synthase (echinocandins). The first is a fungistatic target vulnerable to resistance development; the second, while a fungicidal target, is not sufficiently different from the host to ensure high selectivity; the third, a fungistatic (Aspergillus) or fungicidal (Candida) target, has limited activity spectrum (gaps: Cryptococcus, emerging fungi) and potential host toxicity that might preclude dose escalation. Drugs aimed at totally new targets are thus needed to increase our chemotherapeutic options and to forestall, alone or in combination chemotherapy, the emergence of drug resistance. Protein N-myristoylation, the cotranslational transfer of the 14-carbon saturated fatty acid myristate from CoA...