Abstract
Previous studies of the oligoacyllysyl (OAK) series acyl-lysyl-lysyl-aminoacyl-lysine-amide, suggested their utility towards generating robust linear lipopeptide-like alternatives to antibiotics, although to date, none exhibited potent broad-spectrum bactericidal activity. To follow up on this premise, we produced a new analog (C14KKc12K) and investigated its properties in various media. Mechanistic studies suggest that C14KKc12K uses a non-specific membrane-disruptive mode of action for rapidly reducing viability of Gram-negative bacteria (GNB) similarly to polymyxin B (PMB), a cyclic lipopeptide used as last resort antibiotic. Indeed, C14KKc12K displayed similar affinity for lipopolysaccharides and induced cell permeabilization associated with rapid massive membrane depolarization. Unlike PMB however, C14KKc12K was also bactericidal to Gram-positive bacteria (GPB) at or near the minimal inhibitory concentration (MIC), as assessed against a multispecies panel of >50 strains, displaying MIC50 at 3 and 6 µM, respectively for GPB and GNB. C14KKc12K retained activity in human saliva, reducing the viability of cultivable oral microflora by >99% within two minutes of exposure, albeit at higher concentrations, which, nonetheless, were similar to the commercial gold standard, chlorhexidine. This equipotent bactericidal activity was also observed in pre-formed biofilms of Streptococcus mutans, a major periodontal pathogen. Such compounds therefore, may be useful for eradication of challenging poly-microbial infections.
Highlights
Facing the global crisis of multidrug resistant bacteria[1,2,3,4,5,6], membrane active compounds (MACs) are earning a renewed attention for their potential to control infections[7,8,9,10] by multiple mechanisms, including by affecting critical common bacterial processes such as communication[11, 12] and virulence[13, 14] at sub-inhibitory concentrations
Owing to its hydrophilic attributes, the outer membrane (OM) is often responsible for the low sensitivity of Gram-negative bacteria (GNB) to hydrophobic antimicrobials, thereby further challenging the generation of broad-spectrum antibacterial compounds, needed in poly-microbial infections, for instance
As part of its biophysical characterization, the purified synthetic lipopeptide was first subjected to light scattering measurements in order to assess its potential for self-assembly in an aqueous environment, as compared with two analogs, C12KKc12K and C16KKc12K
Summary
Facing the global crisis of multidrug resistant bacteria[1,2,3,4,5,6], membrane active compounds (MACs) are earning a renewed attention for their potential to control infections[7,8,9,10] by multiple mechanisms, including by affecting critical common bacterial processes such as communication[11, 12] and virulence[13, 14] at sub-inhibitory concentrations. Charge considerations are intricate, namely due to the fact that the relative proportion of anionic phospholipids in bacterial membranes can reach 20–30% in GNB and up to nearly 100% in GPB34, 35 In this respect, the peptidomimetic approach using oligo-acyl-lysines (OAKs) seems suitable for engineering high affinity antibacterial MACs22, 36–38 since OAKs composition consists exclusively of hydrophobic linear acyls and cationic lysine residues[37,38,39], where the inherently simple and incremental nature of designed analogs provides a systematic tool for dissecting the relative importance of charge and/or hydrophobicity. We set out to verify the implied linear relationship (between potency and hydrophobicity) of this C-terminally amidated series by producing a previously untested intermediate analog, C14KKc12K (molecular structure depicted in Fig. 1a) and investigating its antibacterial activity, mode of action and potential application.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
