Broad-spectrum antibiotics indiscriminately kill bacteria, removing nonpathogenic microorganisms and leading to evolution of antibiotic resistant strains. Specific antimicrobials that could selectively kill pathogenic bacteria without targeting other bacteria in the natural microbial community or microbiome may be able to address this concern. In this work, we demonstrate that silver nanoparticles, suitably conjugated to a selective cell wall binding domain (CBD), can efficiently target and selectively kill bacteria. As a relevant example, CBD from Bacillus anthracis selectively bound to B. anthracis in a mixture with Bacillus subtilis, as well in a mixture with Staphylococcus aureus. This new biologically-assisted hybrid strategy, therefore, has the potential to provide selective decontamination of pathogenic bacteria with minimal impact on normal microflora.
Lytic enzymes have been considered
as potential alternatives to antibiotics. These enzymes, particularly
those that target Gram-positive bacteria, consist of modular cell
wall-binding and catalytic domains, which can be shuffled with those
of other lytic enzymes to produce unnatural chimeric enzymes. In this
work, we report the in vitro shuffling of two different modular domains
using a protein self-assembly methodology. Catalytic domains (CD)
and cell wall-binding domains (BD) from the bacteriocin lysostaphin
(Lst) and a putative autolysin from Staphylococcus
aureus (SA1), respectively, were genetically site-specifically
biotinylated and assembled with streptavidin to generate 23 permuted
chimeras. The specific assembly of a CD (3 equiv) and a BD (1 equiv)
from Lst and SA1, respectively [CDL–BDS (3:1)], on a streptavidin scaffold yielded high lytic activity against S. aureus (at least 5.6 log reduction), which
was higher than that obtained with either native Lst or SA1 alone.
Moreover, at 37 °C, the initial rate of cell lysis was over 3-fold
higher than that with free Lst, thereby revealing the unique catalytic
properties of the chimeric proteins. In vitro self-assembly of functional
domains from modular lytic enzymes on a protein scaffold likely expands
the repertoire of bactericidal enzymes with improved activities.
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