Hitting the caspofungin salvage pathway of human-pathogenic fungi with the novel lasso peptide humidimycin (MDN-0010)

• Published in: Antimicrobial agents and chemotherapy Vol. 59; no. 9; pp. 5145 - 5153
• Main Authors: Valiante, Vito, Monteiro, Maria Cândida, Martín, Jesús, Altwasser, Robert, El Aouad, Noureddine, González, Ignacio, Kniemeyer, Olaf, Mellado, Emilia, Palomo, Sara, de Pedro, Nuria, Pérez-Victoria, Ignacio, Tormo, José R, Vicente, Francisca, Reyes, Fernando, Genilloud, Olga, Brakhage, Axel A
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.09.2015
• Subjects: Antifungal Agents; Antifungal Agents - pharmacology; Aspergillus fumigatus; Aspergillus fumigatus - drug effects; Aspergillus fumigatus - metabolism; Cell Wall - drug effects; Cell Wall - metabolism; Echinocandins; Echinocandins - pharmacology; Humans; Lipopeptides; Mechanisms of Action: Physiological Effects; Peptides; Peptides - pharmacology; Signal Transduction - drug effects
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.00683-15

Fungal infections have increased dramatically in the last 2 decades, and fighting infectious diseases requires innovative approaches such as the combination of two drugs acting on different targets or even targeting a salvage pathway of one of the drugs. The fungal cell wall biosynthesis is inhibited by the clinically used antifungal drug caspofungin. This antifungal activity has been found to be potentiated by humidimycin, a new natural product identified from the screening of a collection of 20,000 microbial extracts, which has no major effect when used alone. An analysis of transcriptomes and selected Aspergillus fumigatus mutants indicated that humidimycin affects the high osmolarity glycerol response pathway. By combining humidimycin and caspofungin, a strong increase in caspofungin efficacy was achieved, demonstrating that targeting different signaling pathways provides an excellent basis to develop novel anti-infective strategies.