Antimicrobial peptides
(AMPs) are promising pharmaceutical candidates
for the prevention and treatment of infections caused by multidrug-resistant ESKAPE pathogens, which are responsible for the majority
of hospital-acquired infections. Clinical translation of AMPs has
been limited, in part by apparent toxicity on systemic dosing and
by instability arising from susceptibility to proteolysis. Peptoids
(sequence-specific oligo-N-substituted glycines)
resist proteolytic digestion and thus are of value as AMP mimics.
Only a few natural AMPs such as LL-37 and polymyxin self-assemble
in solution; whether antimicrobial peptoids mimic these properties
has been unknown. Here, we examine the antibacterial efficacy and
dynamic self-assembly in aqueous media of eight peptoid mimics of
cationic AMPs designed to self-assemble and two nonassembling controls.
These amphipathic peptoids self-assembled in different ways, as determined
by small-angle X-ray scattering; some adopt helical bundles, while
others form core–shell ellipsoidal or worm-like micelles. Interestingly,
many of these peptoid assemblies show promising antibacterial, antibiofilm
activity in vitro in media, under host-mimicking conditions and antiabscess
activity in vivo. While self-assembly correlated overall with antibacterial
efficacy, this correlation was imperfect. Certain self-assembled morphologies
seem better-suited for antibacterial activity. In particular, a peptoid
exhibiting a high fraction of long, worm-like micelles showed reduced
antibacterial, antibiofilm, and antiabscess activity against ESKAPE pathogens compared with peptoids that form ellipsoidal
or bundled assemblies. This is the first report of self-assembling
peptoid antibacterials with activity against in vivo biofilm-like
infections relevant to clinical medicine.
Antimicrobial peptides have attracted considerable interest as potential new class of antibiotics against multi-drug resistant bacteria. However, their therapeutic potential is limited, in part due to susceptibility towards enzymatic degradation and low bioavailability. Peptoids (oligomers of N-substituted glycines) demonstrate proteolytic stability and better bioavailability than corresponding peptides while in many cases retaining antibacterial activity. In this study, we synthesized a library of 36 peptoids containing fluorine, chlorine, bromine and iodine atoms, which vary by length and level of halogen substitution in position 4 of the phenyl rings. As we observed a clear correlation between halogenation of an inactive model peptoid and its increased antimicrobial activity, we designed chlorinated and brominated analogues of a known peptoid and its shorter counterpart. Short brominated analogues displayed up to 32-fold increase of the activity against S. aureus and 16- to 64-fold against E. coli and P. aeruginosa alongside reduced cytotoxicity. The biological effect of halogens seems to be linked to the relative hydrophobicity and self-assembly properties of the compounds. By small angle X-ray scattering (SAXS) we have demontrated how the self-assembled structures are dependent on the size of the halogen, degree of substitution and length of the peptoid, and correlated these features to their activity.
Using small angle X-ray and neutron scattering and theoretical modelling we have elucidated the structure of the antimicrobial peptide, indolicidin, and the interaction with model lipid membranes of different anionic lipid compositions mimicking charge densities found in the cytoplasmic membrane of bacteria.
Thermoresponsive amphiphilic biodegradable block copolymers of the type poly(ε-caprolactone-co-lactide)-poly(ethylene glycol)-poly(ε-caprolactone-co-lactide) (PCLA-PEG-PCLA) have great potential for various biomedical applications. In the present study, we have surveyed the effects of PEG spacer length (m = 1000 and 1500), temperature, and polymer concentration on the self-assembling process to form supramolecular structures in aqueous solutions of the PCLA-PEG-PCLA copolymer. This copolymer has a lower critical solution temperature, and the cloud point depends on both concentration and PEG length. Thermoreversible hydrogels are formed in the semidilute regime; the gel windows in the phase diagrams can be tuned by the concentration and length of the PEG spacer. The rheological properties of both dilute and semidilute samples were characterized; especially the sol-to-gel transition was examined. Small-angle neutron scattering (SANS) experiments reveal fundamental structural differences between the two copolymers for both dilute and semidilute samples. The intensity profiles for the copolymer with the long PEG spacer could be described by a spherical core-shell model over a broad temperature domain, whereas the copolymer with the short hydrophilic spacer forms rod-like species over an extended temperature range. This finding is supported by cryo-TEM images. At temperatures approaching macroscopic phase separation, both copolymers seem to assume extended rod-like structures.
The
modulation of conformational flexibility in antimicrobial peptides
(AMPs) has been investigated as a strategy to improve their efficacy
against bacterial pathogens while reducing their toxicity. Here, we
synthesized a library of helicity-modulated antimicrobial peptoids
by the position-specific incorporation of helix-inducing monomers.
The peptoids displayed minimal variations in hydrophobicity, which
permitted the specific assessment of the effect of conformational
differences on antimicrobial activity and selectivity. Among the moderately
helical peptoids, the most dramatic increase in selectivity was observed
in peptoid 17, providing more than a 20-fold increase
compared to fully helical peptoid 1. Peptoid 17 had potent broad-spectrum antimicrobial activity that included clinically
isolated multi-drug-resistant pathogens. Compared to pexiganan AMP, 17 showed superior metabolic stability, which could potentially
reduce the dosage needed, alleviating toxicity. Dye-uptake assays
and high-resolution imaging revealed that the antimicrobial activity
of 17 was, as with many AMPs, mainly due to membrane
disruption. However, the high selectivity of 17 reflected
its unique conformational characteristics, with differential interactions
between bacterial and erythrocyte membranes. Our results suggest a
way to distinguish different membrane compositions solely by helicity
modulation, thereby improving the selectivity toward bacterial cells
with the maintenance of potent and broad-spectrum activity.
Staphylococcus aureus
resistance is a consistent problem with a large impact on the health care system. Infections with resistant
S. aureus
can cause serious adverse effects and can result in death.
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