Abstract

Bioprospecting Natural Products for Potential Anti-fungal Drugs

Lixin Zhang, Professor, Chinese Academy of Sciences

One of the major limiting factors in Natural products drug discovery industry is that pharmaceuticals have been traditionally designed to target individual factors in a disease system, but diseases are complex in nature and vulnerable at multiple attacks.  Therefore, a systematic novel synergistic drug screening approach based on a multifactorial principle is urgently needed5.  Many drugs could be more effective at a reduced dosage if low dosages of other synergistic compounds are introduced simultaneously, especially from our microbial natural product library1,2. To rapidly discover new antifungal agents for drug-resistant pathogens, we developed a high-throughput synergy screening (HTSS) strategy for novel microbial natural products3. Here we report an unexpected consequence of MDR1 upregulation: it confers enhanced sensitivity to the natural product berberine. We show that berberine is indeed highly efficacious in inhibiting the growth of azole-resistant clinical C. albicans isolates, with upregulated MDR1, from HIV infected patients. This effect is at least in part due to enhanced accumulation of berberine inside cells and a number of berberine structural analogues exhibited similar MDR1-dependent antifungal activity. Our study reveals a novel function of MDR1 in increasing sensitivity of drug-resistant fungal pathogens to selected natural products. The production of drugable secondary metabolites from microbial producers could be further increased by synthetic biology approaches. Conclusions. 1. A high quality library validated by structurally diversified bioactive compounds, even with novel MoA.  2. Berberine is highly efficacious in inhibiting the growth of azole-resistant clinical C. albicans isolates, with upregulated MDR1, from HIV infected patients. 3. Engineering of the hrdB gene improved the yield of avermectins4.