Abstract The failure to treat everyday bacterial infections is a current threat as pathogens are finding new ways to thwart antibiotics through mechanisms of resistance and intracellular refuge, thus rendering current antibiotic strategies ineffective. Cell‐penetrating peptides (CPPs) are providing a means to improve antibiotics that are already approved for use. Through coadministration and conjugation of antibiotics with CPPs, improved accumulation and selectivity with alternative and/or additional modes of action against infections have been observed. Herein, we review the recent progress of this antibiotic–cell‐penetrating peptide strategy in combatting sensitive and drug‐resistant pathogens. We take a closer look into the specific antibiotics that have been enhanced, and in some cases repurposed as broad‐spectrum drugs. Through the addition and conjugation of cell‐penetrating peptides to antibiotics, increased permeation across mammalian and/or bacterial membranes and a broader range in bacterial selectivity have been achieved. more »« less
Vasan, Archit Kumar; Haloi, Nandan; Ulrich, Rebecca Joy; Metcalf, Mary Elizabeth; Wen, Po-Chao; Metcalf, William W.; Hergenrother, Paul J.; Shukla, Diwakar; Tajkhorshid, Emad
(, Proceedings of the National Academy of Sciences)
Andrej Sali, Bioengineering &
(Ed.)
Significance Antibiotic resistance in Gram-negative pathogens has been identified as an urgent threat to human health by the World Health Organization. The major challenge with treating infections by these pathogens is developing antibiotics that can traverse the dense bacterial outer membrane (OM) formed by a mesh of lipopolysaccharides. Effective antibiotics permeate through OM porins, which have evolved for nutrient diffusion; however, the conformational states of these porins regulating permeation are still unclear. Here, we used molecular dynamics simulations, free energy calculations, Markov-state modeling, and whole-cell accumulation assays to provide mechanistic insight on how a porin shifts between open and closed states. We provide a mechanism of how Gram-negative bacteria confer resistance to antibiotics.
Glass, Emma M; Dillard, Lillian R; Kolling, Glynis L; Warren, Andrew S; Papin, Jason A
(, PLOS Biology)
Bollenbach, Tobias
(Ed.)
Bacterial pathogens pose a major risk to human health, leading to tens of millions of deaths annually and significant global economic losses. While bacterial infections are typically treated with antibiotic regimens, there has been a rapid emergence of antimicrobial resistant (AMR) bacterial strains due to antibiotic overuse. Because of this, treatment of infections with traditional antimicrobials has become increasingly difficult, necessitating the development of innovative approaches for deeply understanding pathogen function. To combat issues presented by broad- spectrum antibiotics, the idea of narrow-spectrum antibiotics has been previously proposed and explored. Rather than interrupting universal bacterial cellular processes, narrow-spectrum antibiotics work by targeting specific functions or essential genes in certain species or subgroups of bacteria. Here, we generate a collection of genome-scale metabolic network reconstructions (GENREs) of pathogens through an automated computational pipeline. We used these GENREs to identify subgroups of pathogens that share unique metabolic phenotypes and determined that pathogen physiological niche plays a role in the development of unique metabolic function. For example, we identified several unique metabolic phenotypes specific to stomach pathogens. We identified essential genes unique to stomach pathogens in silico and a corresponding inhibitory compound for a uniquely essential gene. We then validated our in silico predictions with an in vitro microbial growth assay. We demonstrated that the inhibition of a uniquely essential gene,thyX, inhibited growth of stomach-specific pathogens exclusively, indicating possible physiological location-specific targeting. This pioneering computational approach could lead to the identification of unique metabolic signatures to inform future targeted, physiological location-specific, antimicrobial therapies, reducing the need for broad-spectrum antibiotics.
The discovery of cell penetrating peptides (CPPs) with unique membrane activity has inspired the design and synthesis of a variety of cell penetrating macromolecules, which offer tremendous opportunity and promise for intracellular delivery of a variety of imaging probes and therapeutics. While cell penetrating macromolecules can be designed and synthesized to have equivalent or even superior cell penetrating activity compared with natural CPPs, most of them suffer from moderate to severe cytotoxicity. Inspired by recent advances in peptide self-assembly and cell penetrating macromolecules, in this work, we demonstrated a new class of peptide assemblies with intrinsic cell penetrating activity and excellent cytocompatibility. Supramolecular assemblies were formed through the self-assembly of de novo designed multidomain peptides (MDPs) with a general sequence of K x (QW) 6 E y in which the numbers of lysine and glutamic acid can be varied to control supramolecular assembly, morphology and cell penetrating activity. Both supramolecular spherical particles and nanofibers exhibit much higher cell penetrating activity than monomeric MDPs while supramolecular nanofibers were found to further enhance the cell penetrating activity of MDPs. In vitro cell uptake results suggested that the supramolecular cell penetrating nanofibers undergo macropinocytosis-mediated internalization and they are capable of escaping from the lysosome to reach the cytoplasm, which highlights their great potential as highly effective intracellular therapeutic delivery vehicles and imaging probes.
Abstract Antibiotic‐resistant infections caused by bacterial pathogens pose a serious threat to public health, hampering wound healing and causing significant morbidities worldwide. A biomedical fiber‐device that functions as a drugless antiseptic is introduced as a solution to this problem. Through stitching, piercing, or topical application to the wound, this fiber slows down the proliferation of pathogenic bacteria, thereby reducing the risks associated with inflammation and inhibiting infections. The fiber's bacterial proliferation inhibition function is based on the galvanic effect, which disturbs bacterial quorum sensing. Detailed herein are the fiber design optimization, scalable fabrication approach, electrical function characterization, and antiseptic function verification in cultures of typical wound pathogens. Such a fiber—mechanically and environmentally resilient, insensitive to harsh storage conditions with nominally infinite shelf‐life, resulting from machining rather than pharmacochemical fabrication— provides a cost‐effective and widely available alternative to current antibiotic treatments of physical injury.
Aduru, Sai Varun; Szenkiel, Karolina; Rahman, Anika; Ahmad, Mehrose; Fabozzi, Maya; Smith, Robert P.; Lopatkin, Allison J.
(, Microbiology Spectrum)
Zhang, Xue
(Ed.)
ABSTRACT Bacterial growth and metabolic rates are often closely related. However, under antibiotic selection, a paradox in this relationship arises: antibiotic efficacy decreases when bacteria are metabolically dormant, yet antibiotics select for resistant cells that grow fastest during treatment. That is, antibiotic selection counterintuitively favors bacteria with fast growth but slow metabolism. Despite this apparent contradiction, antibiotic resistant cells have historically been characterized primarily in the context of growth, whereas the extent of analogous changes in metabolism is comparatively unknown. Here, we observed that previously evolved antibiotic-resistant strains exhibited a unique relationship between growth and metabolism whereby nutrient utilization became more efficient, regardless of the growth rate. To better understand this unexpected phenomenon, we used a simplified model to simulate bacterial populations adapting to sub-inhibitory antibiotic selection through successive bottlenecking events. Simulations predicted that sub-inhibitory bactericidal antibiotic concentrations could select for enhanced metabolic efficiency, defined based on nutrient utilization: drug-adapted cells are able to achieve the same biomass while utilizing less substrate, even in the absence of treatment. Moreover, simulations predicted that restoring metabolic efficiency would re-sensitize resistant bacteria exhibiting metabolic-dependent resistance; we confirmed this result using adaptive laboratory evolutions ofEscherichia coliunder carbenicillin treatment. Overall, these results indicate that metabolic efficiency is under direct selective pressure during antibiotic treatment and that differences in evolutionary context may determine both the efficacy of different antibiotics and corresponding re-sensitization approaches. IMPORTANCEThe sustained emergence of antibiotic-resistant pathogens combined with the stalled drug discovery pipelines highlights the critical need to better understand the underlying evolution mechanisms of antibiotic resistance. To this end, bacterial growth and metabolic rates are often closely related, and resistant cells have historically been characterized exclusively in the context of growth. However, under antibiotic selection, antibiotics counterintuitively favor cells with fast growth, and slow metabolism. Through an integrated approach of mathematical modeling and experiments, this study thereby addresses the significant knowledge gap of whether antibiotic selection drives changes in metabolism that complement, and/or act independently, of antibiotic resistance phenotypes.
Zeiders, Samantha M., and Chmielewski, Jean. Antibiotic–cell‐penetrating peptide conjugates targeting challenging drug‐resistant and intracellular pathogenic bacteria. Chemical Biology & Drug Design 98.5 Web. doi:10.1111/cbdd.13930.
Zeiders, Samantha M., and Chmielewski, Jean.
"Antibiotic–cell‐penetrating peptide conjugates targeting challenging drug‐resistant and intracellular pathogenic bacteria". Chemical Biology & Drug Design 98 (5). Country unknown/Code not available: Wiley-Blackwell. https://doi.org/10.1111/cbdd.13930.https://par.nsf.gov/biblio/10359781.
@article{osti_10359781,
place = {Country unknown/Code not available},
title = {Antibiotic–cell‐penetrating peptide conjugates targeting challenging drug‐resistant and intracellular pathogenic bacteria},
url = {https://par.nsf.gov/biblio/10359781},
DOI = {10.1111/cbdd.13930},
abstractNote = {Abstract The failure to treat everyday bacterial infections is a current threat as pathogens are finding new ways to thwart antibiotics through mechanisms of resistance and intracellular refuge, thus rendering current antibiotic strategies ineffective. Cell‐penetrating peptides (CPPs) are providing a means to improve antibiotics that are already approved for use. Through coadministration and conjugation of antibiotics with CPPs, improved accumulation and selectivity with alternative and/or additional modes of action against infections have been observed. Herein, we review the recent progress of this antibiotic–cell‐penetrating peptide strategy in combatting sensitive and drug‐resistant pathogens. We take a closer look into the specific antibiotics that have been enhanced, and in some cases repurposed as broad‐spectrum drugs. Through the addition and conjugation of cell‐penetrating peptides to antibiotics, increased permeation across mammalian and/or bacterial membranes and a broader range in bacterial selectivity have been achieved.},
journal = {Chemical Biology & Drug Design},
volume = {98},
number = {5},
publisher = {Wiley-Blackwell},
author = {Zeiders, Samantha M. and Chmielewski, Jean},
}
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