Vancomycin mimicry: towards new supramolecular antibiotics

Flint, Alister J; Davis, Anthony P.

doi:10.1039/d2ob01381a

Cited by 11 publications

(6 citation statements)

References 110 publications

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“…aureus, the cell wall is primarily composed of peptidoglycan and other molecules, such as lipopeptides, forming a robust protective layer. The d -Ala- d -Ala sequence is a component of the peptidoglycan precursor and serves as a target site for numerous antibiotics, including β-lactams like penicillin and glycopeptides such as vancomycin. , Vancomycin, a large-ring glycopeptide antibiotic, possesses a complex cyclic structure that is crucial for forming a specific three-dimensional conformation, enabling its binding to the d -Ala- d -Ala sequence . The three-dimensional structure of vancomycin is highly complementary to the spatial structure of the d -Ala- d -Ala sequence, facilitating a precise “docking” interaction .…”

Section: Resultsmentioning

confidence: 99%

Targeted Light-Induced Immunomodulatory Strategy for Implant-Associated Infections via Reversing Biofilm-Mediated Immunosuppression

Jiang,

Wang,

Ren

et al. 2024

ACS Nano

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The clinical treatment efficacy for implant-associated infections (IAIs), particularly those caused by Methicillin-resistant Staphylococcus aureus (MRSA), remains unsatisfactory, primarily due to the formation of biofilm barriers and the resulting immunosuppressive microenvironment, leading to the chronicity and recurrence of IAIs. To address this challenge, we propose a light-induced immune enhancement strategy, synthesizing BSA@MnO 2 @Ce6@Van (BMCV). The BMCV exhibits precise targeting and adhesion to the S. aureus biofilm-infected region, coupled with its capacity to catalyze oxygen generation from H 2 O 2 in the hypoxic and acidic biofilm microenvironment (BME), promoting oxygen-dependent photodynamic therapy efficacy while ensuring continuous release of manganese ions. Notably, targeted BMCV can penetrate biofilms, producing ROS that degrade extracellular DNA, disrupting the biofilm structure and impairing its barrier function, making it vulnerable to infiltration and elimination by the immune system. Furthermore, light-induced reactive oxygen species (ROS) around the biofilm can lyse S. aureus, triggering bacterium-like immunogenic cell death (ICD), releasing abundant immune costimulatory factors, facilitating the recognition and maturation of antigenpresenting cells (APCs), and activating adaptive immunity. Additionally, manganese ions in the BME act as immunoadjuvants, further amplifying macrophage-mediated innate and adaptive immune responses and reversing the immunologically cold BME to an immunologically hot BME. We prove that our synthesized BMCV elicits a robust adaptive immune response in vivo, effectively clearing primary IAIs and inducing long-term immune memory to prevent recurrence. Our study introduces a potent light-induced immunomodulatory nanoplatform capable of reversing the biofilm-induced immunosuppressive microenvironment and disrupting biofilm-mediated protective barriers, offering a promising immunotherapeutic strategy for addressing challenging S. aureus IAIs.

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Section: Resultsmentioning

confidence: 99%

Targeted Light-Induced Immunomodulatory Strategy for Implant-Associated Infections via Reversing Biofilm-Mediated Immunosuppression

Jiang,

Wang,

Ren

et al. 2024

ACS Nano

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“…One of the current groups of strategies is based on “fine-tuning” the old antibiotics by modifying their chemical structure. Such approaches have been successfully implemented for, e.g., cephalosporin [ 273 ], tetracycline [ 274 ], vancomycin [ 275 , 276 , 277 , 278 ], and others [ 253 ]. Other approaches encompass strategies that enhance the efficacy of antibiotics through modulation of the bacterial metabolism or improving antibiotics delivery systems [ 256 ].…”

Section: At the Dawn Of The Post-antibiotic Era?mentioning

confidence: 99%

Antibiotics and Bacterial Resistance—A Short Story of an Endless Arms Race

Baran

Kwiatkowska

Potocki

2023

IJMS

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Despite the undisputed development of medicine, antibiotics still serve as first-choice drugs for patients with infectious disorders. The widespread use of antibiotics results from a wide spectrum of their actions encompassing mechanisms responsible for: the inhibition of bacterial cell wall biosynthesis, the disruption of cell membrane integrity, the suppression of nucleic acids and/or proteins synthesis, as well as disturbances of metabolic processes. However, the widespread availability of antibiotics, accompanied by their overprescription, acts as a double-edged sword, since the overuse and/or misuse of antibiotics leads to a growing number of multidrug-resistant microbes. This, in turn, has recently emerged as a global public health challenge facing both clinicians and their patients. In addition to intrinsic resistance, bacteria can acquire resistance to particular antimicrobial agents through the transfer of genetic material conferring resistance. Amongst the most common bacterial resistance strategies are: drug target site changes, increased cell wall permeability to antibiotics, antibiotic inactivation, and efflux pumps. A better understanding of the interplay between the mechanisms of antibiotic actions and bacterial defense strategies against particular antimicrobial agents is crucial for developing new drugs or drug combinations. Herein, we provide a brief overview of the current nanomedicine-based strategies that aim to improve the efficacy of antibiotics.

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“…More importantly, peptidomimetics hold significant promise in the fight against AMR as they exhibit enhanced antimicrobial potency against broad-spectrum microorganisms and can circumvent various mechanisms that make pathogens resistant to conventional antibiotics and AMPs ( Kuppusamy et al, 2019 ; Molchanova et al, 2017 ; Qvit et al, 2017 ). Several peptidomimetics with unique structural scaffolds, such as peptoids, α-peptides, peptoid hybrids, and β-peptoids, have been reported ( Flint & Davis, 2022 ; Ghosh & Haldar, 2015 ; Karlsson et al, 2010 ; Kuppusamy et al, 2019 ; Makobongo et al, 2012 ; Molchanova et al, 2017 ; Olsen et al, 2007 ; Srinivas et al, 2010 ). Several approaches are used to generate peptidomimetics ( Figure 6 ), enabling researchers to design and synthesize compounds with peptide-like characteristics but improved properties, such as enhanced stability, bioavailability, or target selectivity.…”

Section: Designing Antimicrobial Peptidesmentioning

confidence: 99%

Design Methods for Antimicrobial Peptides with Improved Performance

Mwangi,

Kamau,

Thuku

et al. 2023

Zoological Research

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The recalcitrance of pathogens to traditional antibiotics has made treating and eradicating bacterial infections more difficult. In this regard, developing new antimicrobial agents to combat antibiotic-resistant strains has become a top priority. Antimicrobial peptides (AMPs), a ubiquitous class of naturally occurring compounds with broad-spectrum antipathogenic activity, hold significant promise as an effective solution to the current antimicrobial resistance (AMR) crisis. Several AMPs have been identified and evaluated for their therapeutic application, with many already in the drug development pipeline. Their distinct properties, such as high target specificity, potency, and ability to bypass microbial resistance mechanisms, make AMPs a promising alternative to traditional antibiotics. Nonetheless, several challenges, such as high toxicity, lability to proteolytic degradation, low stability, poor pharmacokinetics, and high production costs, continue to hamper their clinical applicability. Therefore, recent research has focused on optimizing the properties of AMPs to improve their performance. By understanding the physicochemical properties of AMPs that correspond to their activity, such as amphipathicity, hydrophobicity, structural conformation, amino acid distribution, and composition, researchers can design AMPs with desired and improved performance. In this review, we highlight some of the key strategies used to optimize the performance of AMPs, including rational design and de novo synthesis. We also discuss the growing role of predictive computational tools, utilizing artificial intelligence and machine learning, in the design and synthesis of highly efficacious lead drug candidates.

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Vancomycin mimicry: towards new supramolecular antibiotics

Abstract: Efforts to bind C-terminal d-Ala–d-Ala, mimicking the action of vancomycin, could lead to valuable new antibiotics with prolonged clinical effectiveness.

Cited by 11 publications

References 110 publications

Targeted Light-Induced Immunomodulatory Strategy for Implant-Associated Infections via Reversing Biofilm-Mediated Immunosuppression

Targeted Light-Induced Immunomodulatory Strategy for Implant-Associated Infections via Reversing Biofilm-Mediated Immunosuppression

Antibiotics and Bacterial Resistance—A Short Story of an Endless Arms Race

Design Methods for Antimicrobial Peptides with Improved Performance

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