Solid-state NMR Reveals Reorganization of the Aspergillus fumigatus Cell Wall Due to a Host-Defence Peptide

The limited availability of antifungal drug treatments and the rising issue of drug resistance highlight the urgent need for new antifungal drugs to combat drug-resistant Aspergillus fumigatus. The host-defence peptide cathelicidin-2 has demonstrated a significant inhibitory effect on azole-resistant Aspergillus fumigatus but its mechanism of action remains elusive. We applied a tailored set 1H and 13C detected solid state nuclear magnetic resonance experiments to elucidate the cell wall composition of Aspergillus fumigatus and to shed light on the mechanism of action of the peptide within the cell wall. Our results revealed that presence of the peptide affects galactosaminogalactan, an important component involved in the pathogenesis of invasive aspergillosis, as well as other specific polysaccharides and amino acids within the mobile cell wall domain. At longer exposure times, the peptide also influences the rigid cell wall domains by enhancing water penetration into the hydrophobic rigid cell wall domain. The findings reveal how the peptide can reach the plasma membrane and may aid the design of novel antifungal drugs with enhanced efficacy.