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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.
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This content will become publicly available on November 18, 2025
Niche-specific metabolic phenotypes can be used to identify antimicrobial targets in pathogens
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.
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- Award ID(s):
- 2021791
- PAR ID:
- 10628499
- Editor(s):
- Bollenbach, Tobias
- Publisher / Repository:
- PLOS
- Date Published:
- Journal Name:
- PLOS Biology
- Volume:
- 22
- Issue:
- 11
- ISSN:
- 1545-7885
- Page Range / eLocation ID:
- e3002907
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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