Abstract
Cyclic lipo(depsi)peptides (CLiPs) from Pseudomonas constitute a class of natural products involved in a broad range of biological functions for their producers. They also display interesting antimicrobial potential including activity against Gram-positive bacteria. Literature has indicated that these compounds can induce membrane permeabilization, possibly through pore-formation, leading to the general view that the cellular membrane constitutes the primary target in their mode of action. In support of this view, we previously demonstrated that the enantiomer of pseudodesmin A, a member of the viscosin group of CLiPs, shows identical activity against a test panel of six Gram-positive bacterial strains. Here, a previously developed total organic synthesis route is used and partly adapted to generate 20 novel pseudodesmin A analogs in an effort to derive links between molecular constitution, structure and activity. From these, the importance of a macrocycle closed by an ester bond as well as a critical length of β-OH fatty acid chain capping the N-terminus is conclusively demonstrated, providing further evidence for the importance of peptide-membrane interactions in the mode of action. Moreover, an alanine scan is used to unearth the contribution of specific amino acid residues to biological activity. Subsequent interpretation in terms of a structural model describing the location and orientation of pseudodesmin A in a membrane environment, allows first insight in the peptide-membrane interactions involved. The biological screening also identified residue positions that appear less sensitive to conservative modifications, allowing the introduction of a non-perturbing tryptophan residue which will pave the way toward biophysical studies using fluorescence spectroscopy.
Highlights
Antimicrobial resistance is eroding the utility of today’s antibiotics and fuels the renewed drive to discover new antibiotics (Bax et al, 1998; Fischbach and Walsh, 2009; Breidenstein et al, 2011; Laxminarayan et al, 2013)
We have previously reported the three-dimensional structure of the 2 neutral subgroup representatives, viscosinamide A (D0) (Geudens et al, 2014) and pseudodesmin A (L0) (Sinnaeve et al, 2009a,b), while that of anionic WLIP (D−) was already available from literature (Han et al, 1992)
By developing a total chemical synthesis route to viscosin group members, we demonstrated that the biological activity of the enantiomer of PsdA (2) is identical to the natural compound (1), apparently excluding a receptor based interaction as the determining factor for biological activity further substantiating the membrane as the primary target (De Vleeschouwer et al, 2014)
Summary
Antimicrobial resistance is eroding the utility of today’s antibiotics and fuels the renewed drive to discover new antibiotics (Bax et al, 1998; Fischbach and Walsh, 2009; Breidenstein et al, 2011; Laxminarayan et al, 2013). The archetypal AMP consists of a linear oligopeptide sequence bearing cationic and hydrophobic residues with a sequence and spatial distribution that generates amphipathic properties once properly folded (Bradshaw, 2003; Jenssen et al, 2006; Huang et al, 2010; Bahar and Ren, 2013). Such folding occurs as part of a variety of modes of action whereby interaction with the bacterial membrane perturbs the latter, causing lysis and killing the bacteria. In contrast to well-known classes of AMPs, their biosynthesis involves large multi-domain, non-ribosomal peptide synthetases (Raaijmakers et al, 2010; Süssmuth and Mainz, 2017; Götze and Stallforth, 2019), capable of introducing these features as well as the presence of non-proteinogenic amino acids
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.