Small-molecule targeting of a diapophytoene desaturase inhibits S. aureus virulence

Abstract

The surge of antibiotic resistance in Staphylococcus aureus has created a dire need for innovative anti-infective agents that attack new targets, to overcome resistance. In S. aureus, carotenoid pigment is an important virulence factor because it shields the bacterium from host oxidant killing. Here we show that naftifine, a US Food and Drug Administration (FDA)-approved antifungal drug, blocks biosynthesis of carotenoid pigment at nanomolar concentrations. This effect is mediated by competitive inhibition of S. aureus diapophytoene desaturase (CrtN), an essential enzyme for carotenoid pigment synthesis. We found that naftifine attenuated the virulence of a variety of clinical S. aureus isolates, including methicillin-resistant S. aureus (MRSA) strains, in mouse infection models. Specifically, we determined that naftifine is a lead compound for potent CrtN inhibitors. In sum, these findings reveal that naftifine could serve as a chemical probe to manipulate CrtN activity, providing proof of concept that CrtN is a druggable target against S. aureus infections.

Virulence Factor Targeting of the Bacterial Pathogen Staphylococcus aureus for Vaccine and Therapeutics

“…Screening for staphyloxanthin inhibition can be accomplished by treating S. aureus with the compound of interest, and then observing the decrease in golden color [206]. Recently Chen and colleagues used that approach to screen 412 drugs to find drugs which inhibited staphyloxanthin biosynthesis [206].…”

“…Recently Chen and colleagues used that approach to screen 412 drugs to find drugs which inhibited staphyloxanthin biosynthesis [206]. They were able to find three compounds that resulted in the loss of pigmentation in S. aureus Newman, ibandronate, terbinafine and naftifine the last of which inhibited staphyloxanthin production most significantly [206]. Bacteria treated with naftifine exhibited increased sensitivity to hydrogen peroxide, and were 20 fold decreased in survival in human whole blood [206].…”

Pharmacological Targeting of the Host–Pathogen Interaction: Alternatives to Classical Antibiotics to Combat Drug-Resistant Superbugs

“…Interestingly, the next enzyme in the S. aureus carotenoid pigment synthesis pathway is the diapophytoene desaturase, CrtN, which is inhibited by nanomolar concentrations by the FDA-approved antifungal drug, naftifine. Pigment inhibition by naftidine treatment decreased bacterial burden and increased mouse survival in systemic S. aureus challenge model [52]. Blocking carotenoid synthesis also increased cell membrane fluidity to sensitize S. aureus to the antimicrobial action of cationic host defense peptides [53].…”

Targeting fundamental pathways to disrupt Staphylococcus aureus survival: clinical implications of recent discoveries

“…Staphyloxanthin, the eponymous feature of S. aureus, is a C30 triterpenoid carotenoid thought to scavenge free radicals with conjugated double bonds (107) and promote resistance to cationic antimicrobial peptide killing by increasing bacterial membrane rigidity (108). Staphyloxanthin enhances S. aureus survival in WT mice but not in NADPH oxidase-deficient mice (109,110), and inhibition of staphyloxanthin biosynthesis reduces S. aureus viability in the host, thereby corroborating the antioxidant function of the molecule in pathogenesis (110)(111)(112). Moreover, staphyloxanthin inhibition in these studies was achieved via a small-molecule inhibitor, suggesting potential therapeutic application of such a target.…”