Tuning the Intracellular Bacterial Targeting of Peptidic Vectors

Lei, Eric K.; Pereira, Mark P.; Kelley, Shana O.

doi:10.1002/anie.201302265

Cited by 46 publications

(69 citation statements)

References 20 publications

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“…After its endocytic internalization, the conjugate will be released from the endosomes onto the cytosol to exert its ATB action . Over the past years, this approach has been reported as a promising delivery strategy to enhance the permeability and the ATB activity of drugs against intracellular microbes …”

Section: Trojan Horse Approaches To Overcome Antimicrobial Resistancementioning

confidence: 99%

“…One of the first studies on CPP‐ATB conjugates was conducted by Kelley and his co‐workers in 2013 . In this study, the authors firstly conjugated methotrexate (Mtx, 78 ), a bacteriostatic dihydrofolate reductase inhibitor, with a CPP containing three hydrophobic amino acids (cyclohexylalanine) and three cationic residues ( d ‐arginine) to form the conjugate ( 79 ) (Figure ).…”

Section: Trojan Horse Approaches To Overcome Antimicrobial Resistancementioning

confidence: 99%

“…In this study, the authors firstly conjugated methotrexate (Mtx, 78 ), a bacteriostatic dihydrofolate reductase inhibitor, with a CPP containing three hydrophobic amino acids (cyclohexylalanine) and three cationic residues ( d ‐arginine) to form the conjugate ( 79 ) (Figure ). The latter exhibited good inhibitory action against the opportunistic intracellular pathogen Listeria monocytogenes (L. monocytogenes) , a slight improvement when compared to the unconjugated ATB Mtx ( 78 ) (MIC 50 of 3.7 ± 0.2 and 8.8 ± 0.9 µM, respectively) . Interestingly, when tested against HeLa cells infected with L. monocytogenes , ( 79 ) retained ATB activity towards the intracellular pathogens, while presenting with less toxicity to the host cells than the parent antibiotic .…”

Section: Trojan Horse Approaches To Overcome Antimicrobial Resistancementioning

confidence: 99%

“…The latter exhibited good inhibitory action against the opportunistic intracellular pathogen Listeria monocytogenes (L. monocytogenes) , a slight improvement when compared to the unconjugated ATB Mtx ( 78 ) (MIC 50 of 3.7 ± 0.2 and 8.8 ± 0.9 µM, respectively) . Interestingly, when tested against HeLa cells infected with L. monocytogenes , ( 79 ) retained ATB activity towards the intracellular pathogens, while presenting with less toxicity to the host cells than the parent antibiotic . Based on this result, the authors assessed the impact of peptide charge and hydrophobicity on the ATB activity of a series of CPP‐Mtx conjugates.…”

Section: Trojan Horse Approaches To Overcome Antimicrobial Resistancementioning

confidence: 99%

“…Based on this result, the authors assessed the impact of peptide charge and hydrophobicity on the ATB activity of a series of CPP‐Mtx conjugates. Consequently, the peptide charge was increased by adding d ‐arginine residues, whereas the peptide hydrophobicity was modified by substituting cyclohexylalanine with less hydrophobic residues and was characterized by measuring retention time through HPLC with a C18 reverse‐phase column . The biological results revealed that the conjugate ( 80 ) (Figure ), with an increased positive charge and a similar hydrophobicity when compared to the initial conjugate ( 79 ), showed the best ATB profile among studied CPP‐Mtx conjugates.…”

Section: Trojan Horse Approaches To Overcome Antimicrobial Resistancementioning

confidence: 99%

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Drug delivery systems designed to overcome antimicrobial resistance

Pham

Loupias

Dassonville‐Klimpt

et al. 2019

Medicinal Research Reviews

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Antimicrobial resistance has emerged as a huge challenge to the effective treatment of infectious diseases. Aside from a modest number of novel anti‐infective agents, very few new classes of antibiotics have been successfully developed for therapeutic use. Despite the research efforts of numerous scientists, the fight against antimicrobial (ATB) resistance has been a longstanding continued effort, as pathogens rapidly adapt and evolve through various strategies, to escape the action of ATBs. Among other mechanisms of resistance to antibiotics, the sophisticated envelopes surrounding microbes especially form a major barrier for almost all anti‐infective agents. In addition, the mammalian cell membrane presents another obstacle to the ATBs that target intracellular pathogens. To negotiate these biological membranes, scientists have developed drug delivery systems to help drugs traverse the cell wall; these are called “Trojan horse” strategies. Within these delivery systems, ATB molecules can be conjugated with one of many different types of carriers. These carriers could include any of the following: siderophores, antimicrobial peptides, cell‐penetrating peptides, antibodies, or even nanoparticles. In recent years, the Trojan horse‐inspired delivery systems have been increasingly reported as efficient strategies to expand the arsenal of therapeutic solutions and/or reinforce the effectiveness of conventional ATBs against drug‐resistant microbes, while also minimizing the side effects of these drugs. In this paper, we aim to review and report on the recent progress made in these newly prevalent ATB delivery strategies, within the current context of increasing ATB resistance.

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Section: Trojan Horse Approaches To Overcome Antimicrobial Resistancementioning

confidence: 99%

Section: Trojan Horse Approaches To Overcome Antimicrobial Resistancementioning

confidence: 99%

Section: Trojan Horse Approaches To Overcome Antimicrobial Resistancementioning

confidence: 99%

Section: Trojan Horse Approaches To Overcome Antimicrobial Resistancementioning

confidence: 99%

Section: Trojan Horse Approaches To Overcome Antimicrobial Resistancementioning

confidence: 99%

See 3 more Smart Citations

Drug delivery systems designed to overcome antimicrobial resistance

Pham

Loupias

Dassonville‐Klimpt

et al. 2019

Medicinal Research Reviews

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An AIEgen‐Peptide Conjugate as a Phototheranostic Agent for Phagosome‐Entrapped Bacteria

Liu

et al. 2019

Angewandte Chemie

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The detection and elimination of intracellular bacteria remain a major challenge. In this work, we report an aggregation‐induced emission (AIE) bioprobe that can detect bacterial infection and kill bacteria surviving inside macrophages through a dynamic process, notably specific molecular tailoring of the probe by caspase‐1 activation in infected macrophages and accumulation of the residue on phagosomes containing bacteria, leading to light‐up fluorescent signals. Moreover, the AIEgen can serve as a photosensitizer for generation of reactive oxygen species (ROS); and the average ROS indicator fluorescent signal intensity per unit area in the bacterial phagosomes is approximately 2.7‐fold higher than that in the cytoplasm. This, in turn, induces bacteria killing with high efficiency and minimal cytotoxicity towards macrophages. We envision that this specific light‐up bioprobe may provide a new approach for selective and sensitive detection and eradication of intracellular bacterial infections.

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Guiding Drugs to Target‐Harboring Organelles: Stretching Drug‐Delivery to a Higher Level of Resolution

2019

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The ratio between the dose of drug required for optimal efficacy and the dose that causes toxicity is referred to as the therapeutic window. This ratio can be increased by directing the drug to the diseased tissue or pathogenic cell. For drugs targeting fungi and malignant cells, the therapeutic window can be further improved by increasing the resolution of drug delivery to the specific organelle that harbors the drug's target. Organelle targeting is challenging and is, therefore, an under‐exploited strategy. Here we provide an overview of recent advances in control of the subcellular distribution of small molecules with the focus on chemical modifications. Highlighted are recent examples of active and passive organelle‐specific targeting by incorporation of organelle‐directing molecular determinants or by chemical modifications of the pharmacophore. The outstanding potential that lies in the development of organelle‐specific drugs is becoming increasingly apparent.

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Tuning the Intracellular Bacterial Targeting of Peptidic Vectors

Cited by 46 publications

References 20 publications

Drug delivery systems designed to overcome antimicrobial resistance

Drug delivery systems designed to overcome antimicrobial resistance

An AIEgen‐Peptide Conjugate as a Phototheranostic Agent for Phagosome‐Entrapped Bacteria

Guiding Drugs to Target‐Harboring Organelles: Stretching Drug‐Delivery to a Higher Level of Resolution

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