Candidiasis and HIV-Protease Inhibitors: The Expected and the Unexpected

What is largely known is that HIV-protease inhibitors (HIV-PI) have substantially contributed to the reduction of morbidity and mortality presently enjoyed by AIDS patients under highly active antiretroviral therapy (HAART). What is much less known is that they share rather remarkable inhibitory properties against a large panel of pathogenic microorganisms for which aspartyl proteinases (AP) play a critical host-aggressive role. This review focuses on structural and enzymatic properties of aspartyl- and other proteinases in the search of a rationale to address and explain their rather wide and previously unsuspected antimicrobial properties. Special emphasis is here placed on secretory AP of Candida albicans that has been the first of AP category being demonstrated to be affected by HIV-PI. It gathers the multifaceted evidence suggesting that direct AP inhibition by HIV-PI contained in HAART regimens plays a role in the early and potent activity exerted by these inhibitors against mucosal candidiasis. Mostly on the basis of detailed structural and sequence homology consideration, the review also discusses the possibility that more specific and potent protease inhibitors could constitute a new class of antimicrobials targeting virulence rather than microbial growth and so expanding the spectrum of active therapeutics in an era of threatening antimicrobial drug resistance and shortage of new, efficacious antimicrobials.