The cyclic depsipeptide, teixobactin, kills a number of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), and Mycobacterium tuberculosis without detectable resistance. To date, teixobactin is the only molecule in its class that has shown in vivo antibacterial efficacy. In this work, we designed and synthesized 10 new in vivo ready teixobactin analogues. These analogues showed highly potent antibacterial activities against Staphylococcus aureus, MRSA, and vancomycin-resistant enterococci (VRE) in vitro. One analogue, d-Arg-Leu-teixobactin, 2, was found to be noncytotoxic in vitro and in vivo. Moreover, topical instillation of peptide 2 in a mouse model of S. aureus keratitis decreased the bacterial bioburden (>99.0% reduction) and corneal edema significantly as compared to untreated mouse corneas. Collectively, our results have established the high therapeutic potential of a teixobactin analogue in attenuating bacterial infections and associated severities in vivo.
The mammalian and microbial cell selectivity of synthetic and biosynthetic cationic polymers has been investigated. Among the polymers with peptide backbones, polymers containing amino side chains display greater antimicrobial activity than those with guanidine side chains, whereas ethylenimines display superior activity over allylamines. The biosynthetic polymer ε-polylysine (εPL) is noncytotoxic to primary human dermal fibroblasts at concentrations of up to 2,000 μg/ml, suggesting that the presence of an isopeptide backbone has greater cell selectivity than the presence of α-peptide backbones. Both εPL and linear polyethylenimine (LPEI) exhibit bactericidal properties by depolarizing the cytoplasmic membrane and disrupt preformed biofilms. εPL displays broad-spectrum antimicrobial properties against antibiotic-resistant Gram-negative and Gram-positive strains and fungi. εPL elicits rapid bactericidal activity against both Gram-negative and Gram-positive bacteria, and its biocompatibility index is superior to those of cationic antiseptic agents and LPEI. εPL does not interfere with the wound closure of injured rabbit corneas. In a rabbit model of bacterial keratitis, the topical application of εPL (0.3%, wt/vol) decreases the bacterial burden and severity of infections caused by Pseudomonas aeruginosa and Staphylococcus aureus strains. In vivo imaging studies confirm that εPL-treated corneas appeared transparent and nonedematous compared to untreated infected corneas. Taken together, our results highlight the potential of εPL in resolving topical microbial infections.
Protein
flexibility poses a major challenge in binding site identification.
Several computational pocket detection methods that utilize small-molecule
probes in molecular dynamics (MD) simulations have been developed
to address this issue. Although they have proven hugely successful
at reproducing experimental structural data, their ability to predict
new binding sites that are yet to be identified and characterized
has not been demonstrated. Here, we report the use of benzenes as
probe molecules in ligand-mapping MD (LMMD) simulations to predict
the existence of two novel binding sites on the surface of the oncoprotein
MDM2. One of them was serendipitously confirmed by biophysical assays
and X-ray crystallography to be important for the binding of a new
family of hydrocarbon stapled peptides that were specifically designed
to target the other putative site. These results highlight the predictive
power of LMMD and suggest that predictions derived from LMMD simulations
can serve as a reliable basis for the identification of novel ligand
binding sites in structure-based drug design.
Bacterial colonization
of acute and chronic wounds is often associated
with delayed wound healing and prolonged hospitalization. The rise
of multi-drug resistant bacteria and the poor biocompatibility of
topical antimicrobials warrant safe and effective antimicrobials.
Antimicrobial agents that target microbial membranes without interfering
with the mammalian cell proliferation and migration hold great promise
in the treatment of traumatic wounds. This article reports the utility
of superhydrophilic electrospun gelatin nanofiber dressings (NFDs)
containing a broad-spectrum antimicrobial polymer, ε-polylysine
(εPL), crosslinked by polydopamine (pDA) for treating second-degree
burns. In a porcine model of partial thickness burns, NFDs promoted
wound closure and reduced hypertrophic scarring compared to untreated
burns. Analysis of NFDs in contact with the burns indicated that the
dressings trap early colonizers and elicit bactericidal activity,
thus creating a sterile wound bed for fibroblasts migration and re-epithelialization.
In support of these observations, in porcine models of Pseudomonas aeruginosa and Staphylococcus
aureus colonized partial thickness burns, NFDs decreased
bacterial bioburden and promoted wound closure and re-epithelialization.
NFDs displayed superior clinical outcome than standard-of-care silver
dressings. The excellent biocompatibility and antimicrobial efficacy
of the newly developed dressings in pre-clinical models demonstrate
its potential for clinical use to manage infected wounds without compromising
tissue regeneration.
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