New Approaches to Control Infections: Anti-biofilm Strategies against Gram-negative Bacteria

Harrington

et al. 2017

JoVE

Burn infections continue to be an important cause of morbidity and mortality. The increasing emergence of multidrug-resistant (MDR) bacteria has led to the frequent failure of traditional antibiotic treatments. Alternative therapeutics are urgently needed to tackle MDR bacteria. An innovative non-antibiotic approach, antimicrobial blue light (aBL), has shown promising effectiveness against MDR infections. The mechanism of action of aBL is not yet well understood. It is commonly hypothesized that naturally occurring endogenous photosensitizing chromophores in bacteria (e.g., iron-free porphyrins, flavins, etc.) are excited by aBL, which in turn produces cytotoxic reactive oxygen species (ROS) through a photochemical process. Unlike another light-based antimicrobial approach, antimicrobial photodynamic therapy (aPDT), aBL therapy does not require the involvement of an exogenous photosensitizer. All it needs to take effect is the irradiation of blue light; therefore, it is simple and inexpensive. The aBL receptors are the endogenous cellular photosensitizers in bacteria, rather than the DNA. Thus, aBL is believed to be much less genotoxic to host cells than ultraviolet-C (UVC) irradiation, which directly causes DNA damage in host cells. In this paper, we present a protocol to assess the effectiveness of aBL therapy for MDR Acinetobacter baumannii infections in a mouse model of burn injury. By using an engineered bioluminescent strain, we were able to noninvasively monitor the extent of infection in real time in living animals. This technique is also an effective tool for monitoring the spatial distribution of infections in animals.

Section: Introductionmentioning

confidence: 99%

In Vivo Investigation of Antimicrobial Blue Light Therapy for Multidrug-resistant Acinetobacter baumannii Burn Infections Using Bioluminescence Imaging

Harrington

et al. 2017

JoVE

“…This bacterium can form biofilms and thereby increases its resistance towards antibiotic treatment [4], [5]. The bacterial lectin LecB (also called PA-IIL), a virulence factor [6] of P. aeruginosa , is necessary for biofilm formation [7] and its inhibition with carbohydrate ligands results in reduced biofilm growth [8]. The structure of LecB in complex with its monosaccharide ligands l -fucose and d -mannose was determined by X-ray crystallography [9], [10].…”

Section: Introductionmentioning

confidence: 99%

A Biophysical Study with Carbohydrate Derivatives Explains the Molecular Basis of Monosaccharide Selectivity of the Pseudomonas aeruginosa Lectin LecB

2014

Self Cite

The rise of resistances against antibiotics in bacteria is a major threat for public health and demands the development of novel antibacterial therapies. Infections with Pseudomonas aeruginosa are a severe problem for hospitalized patients and for patients suffering from cystic fibrosis. These bacteria can form biofilms and thereby increase their resistance towards antibiotics. The bacterial lectin LecB was shown to be necessary for biofilm formation and the inhibition with its carbohydrate ligands resulted in reduced amounts of biofilm. The natural ligands for LecB are glycosides of d-mannose and l-fucose, the latter displaying an unusual strong affinity. Interestingly, although mannosides are much weaker ligands for LecB, they do form an additional hydrogen bond with the protein in the crystal structure. To analyze the individual contributions of the methyl group in fucosides and the hydroxymethyl group in mannosides to the binding, we designed and synthesized derivatives of these saccharides. We report glycomimetic inhibitors that dissect the individual interactions of their saccharide precursors with LecB and give insight into the biophysics of binding by LecB. Furthermore, theoretical calculations supported by experimental thermodynamic data suggest a perturbed hydrogen bonding network for mannose derivatives as molecular basis for the selectivity of LecB for fucosides. Knowledge gained on the mode of interaction of LecB with its ligands at ambient conditions will be useful for future drug design.

“…In these social colonies the bacteria are protected by a self-formed extracellular matrix and show up to fifteen-fold higher resistance against antibiotics than B. cenocepacia grown in planktonic culture. 5 Like for P. aeruginosa, 6 the inhibition of bacterial biofilm formation could be a promising approach to overcome antibiotic resistance.…”

Section: Introductionmentioning

confidence: 99%

Development of a competitive binding assay for the Burkholderia cenocepacia lectin BC2L-A and structure activity relationship of natural and synthetic inhibitors

et al. 2016

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