Real-time in vivo imaging of invasive- and biomaterial-associated bacterial infections using fluorescently labelled vancomycin

Chloramphenicol (CAP) is one of the most effective antimicrobial agents, but its therapeutic efficacy is greatly limited by its nonspecific distribution and consequent side effects in neutrophils. Targeting to the infection sites, and thus restricting CAP nonselective delivery, provides an alternative way to overcome this limitation. The antibacterial peptide fragment UBI29-41 was identified to have a high bacterial affinity. However, no research so far has been carried out to utilize UBI29-41 as a ligand for bacteria-targeting therapies. In this Article, we first labeled a near-infrared fluorescent dye (ICG02) with UBI29-41 to investigate its targeting capability in different bacteria (S. aureus, E. coli, and P. auruginosa) and bacteria-infected mouse models. Subsequently, UBI29-41 was conjugated with the typical antibiotic (CAP) through the linker glutaric anhydride to form the conjugate CAP-UBI29-41 for the bacteria-targeting therapy. In vitro studies demonstrated the enhanced antibacterial effects of CAP-UBI29-41 on S. aureus and E.coil. Meanwhile, the toxicity of CAP-UBI29-41 on normal cells decreased distinctly in comparison with CAP. Most importantly, CAP-UBI29-41 exhibited more favorable antibacterial efficacy than CAP in bacteria-bearing mouse models. All these results demonstrated that UBI29-41 is an ideal targeting ligand to construct antibacterial agents for bacteria-targeting therapy.

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“…Determination of Minimum InhibitoryConcentrations of CAP-UBI[29][30][31][32][33][34][35][36][37][38][39][40][41] …”

mentioning

confidence: 99%

Bacteria-Targeting Conjugates Based on Antimicrobial Peptide for Bacteria Diagnosis and Therapy

et al. 2015

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“…Targeting ligands include vancomycin which targets peptidoglycans found on Grampositive bacteria, polymyxin which targets lipopolysaccharides found on Gram-negative bacteria, or zinc(II)-bis(dipicolylamine) (ZnDPA) which targets phosphatidylserine found on the surface of both Gram-positive and Gram-negative bacteria (Choi et al 2013;Hanshaw and Smith 2005;Kell et al 2008;Wong et al 2015). Importantly, these ligand targets are not found on the surface of healthy mammalian cells, which allows for specific binding and imaging of bacteria with minimal background signals when using these targeting ligands in vivo (Rice et al 2015;van Oosten et al 2013). Recent novel uses of targeted NPs include the binding and magnetic separation of bacteria from solution to treat bacterial sepsis, by passing NPs through custom-made microfluidic devices (Lee et al 2014).…”

Section: Introductionmentioning

confidence: 99%

Nanoparticle targeting of Gram-positive and Gram-negative bacteria for magnetic-based separations of bacterial pathogens

Yang

Wilson

et al. 2017

Appl Nanosci

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Antimicrobial resistance is a healthcare problem of increasing significance, and there is increasing interest in developing new tools to address bacterial infections. Bacteria-targeting nanoparticles hold promise to improve drug efficacy, compliance, and safety. In addition, nanoparticles can also be used for novel applications, such as bacterial imaging or bioseperations. We here present the use of a scalable block-copolymer-directed self-assembly process, Flash NanoPrecipitation, to form zinc(II)-bis(dipicolylamine) modified nanoparticles that bind to both Grampositive and Gram-negative bacteria with specificity. Particles have tunable surface ligand densities that change particle avidity and binding efficacy. A variety of materials can be encapsulated into the core of the particles, such as optical dyes or iron oxide colloids, to produce imageable and magnetically active bacterial targeting constructs. As a proof-of-concept, these particles are used to bind and separate bacteria from solution in a magnetic column. Magnetic manipulation and separation would translate to a platform for pathogen identification or removal. These magnetic and targeted nanoparticles enable new methods to address bacterial infections.

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“…The vancosamine amine of vancomycin 1 was used to attach a near-IR fluorophore, IRDye 800CW. 158 The resulting adduct 33a was successfully used to image S. aureus myositis (intramuscular infection) in mice. Neither an E. coli infection nor induced inflammation resulted in a signal, demonstrating its specificity for Gram-positive infections.…”

Section: New Glycopeptide Derivativesmentioning

confidence: 99%

Developments in Glycopeptide Antibiotics

et al. 2018

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Glycopeptide antibiotics (GPAs) are a key weapon in the fight against drug resistant bacteria, with vancomycin still a mainstream therapy against serious Gram-positive infections more than 50 years after it was first introduced. New, more potent semisynthetic derivatives that have entered the clinic, such as dalbavancin and oritavancin, have superior pharmacokinetic and target engagement profiles that enable successful treatment of vancomycin-resistant infections. In the face of resistance development, with multidrug resistant (MDR) S. pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA) together causing 20-fold more infections than all MDR Gram-negative infections combined, further improvements are desirable to ensure the Gram-positive armamentarium is adequately maintained for future generations. A range of modified glycopeptides has been generated in the past decade via total syntheses, semisynthetic modifications of natural products, or biological engineering. Several of these have undergone extensive characterization with demonstrated in vivo efficacy, good PK/PD profiles, and no reported preclinical toxicity; some may be suitable for formal preclinical development. The natural product monobactam, cephalosporin, and β-lactam antibiotics all spawned multiple generations of commercially and clinically successful semisynthetic derivatives. Similarly, next-generation glycopeptides are now technically well positioned to advance to the clinic, if sufficient funding and market support returns to antibiotic development.

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Real-time in vivo imaging of invasive- and biomaterial-associated bacterial infections using fluorescently labelled vancomycin

Cited by 250 publications

References 28 publications

Bacteria-Targeting Conjugates Based on Antimicrobial Peptide for Bacteria Diagnosis and Therapy

Bacteria-Targeting Conjugates Based on Antimicrobial Peptide for Bacteria Diagnosis and Therapy

Nanoparticle targeting of Gram-positive and Gram-negative bacteria for magnetic-based separations of bacterial pathogens

Developments in Glycopeptide Antibiotics

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