Therapeutic agents with novel mechanisms of action are urgently needed to counter the emergence of drug-resistant infections. Several decades of research into proteases of disease agents have revealed enzymes well suited for target-based drug development. Among them are the three recently validated proteolytic targets: proteasomes of the malarial parasite Plasmodium falciparum, aspartyl proteases of P. falciparum (plasmepsins) and the Sars-CoV-2 viral proteases. Despite some unfulfilled expectations over previous decades, the three reviewed targets clearly demonstrate that selective protease inhibitors provide effective therapeutic solutions for the two most impacting infectious diseases nowadays-malaria and COVID-19.

• MeSH
• Aspartic Acid Endopeptidases metabolism   MeSH
• COVID-19 enzymology   metabolism   MeSH
• COVID-19 Drug Treatment MeSH
• Protease Inhibitors pharmacology   MeSH
• Humans MeSH
• Malaria drug therapy   enzymology   metabolism   MeSH
• Plasmodium falciparum drug effects   pathogenicity   MeSH
• Proteasome Endopeptidase Complex drug effects   MeSH
• SARS-CoV-2 drug effects   pathogenicity   MeSH
• Drug Development methods   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Lyme disease, a tick-borne illness caused by Borrelia spirochetes, poses a significant threat to public health. While acaricides effectively control ticks on pets and livestock, their impact on pathogen transmission is often unclear. This study investigated the acaricidal efficacy of fipronil against Ixodes ricinus ticks and its potential to block Borrelia afzelii transmission. Initially, we employed the ex vivo membrane blood-feeding system to assess the dose–response acaricidal activity of ivermectin, fipronil and its metabolite fipronil sulfone, when supplemented in the blood meal throughout tick feeding. To obtain the temporal resolution of their acaricidal activity, ticks were allowed to initiate blood feeding on an artificial membrane before being exposed to a 1-time topical application of these acaricides. Fipronil demonstrated superior speed of acaricidal activity, with onset of tick moribundity within a few hours, prompting its selection for further in vivo testing with Borrelia-infected ticks. The I. ricinus nymphs infected with B. afzelii were topically treated with fipronil shortly after attachment to mice. Four weeks post-feeding, the skin and internal organs were examined for the presence of Borrelia. No spirochetes were detected in any organ of mice exposed to fipronil-treated ticks, while 9 out of 10 control mice, exposed to non-treated infectious ticks, displayed Borrelia infection. The in vitro co-culture experiments confirmed that fipronil had no direct effect on Borrelia viability, indicating a tick-directed effect. Overall, these results underline the potential of fipronil as a valuable tool for tick control strategies and suggest a concept for acaricide-mediated Borrelia-transmission blockers.

• MeSH
• Acaricides * pharmacology   MeSH
• Borrelia burgdorferi Group drug effects   physiology   MeSH
• Ixodes * microbiology   drug effects   MeSH
• Lyme Disease * prevention & control   transmission   microbiology   MeSH
• Mice MeSH
• Nymph microbiology   drug effects   MeSH
• Pyrazoles * pharmacology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH